Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia

ABSTRACT

The present invention relates to deuterated 1-piperazino-3-phenyl-indanes and salts thereof with activity at dopamine receptors D 1  and D 2  as well as the 5HT 2  receptors in the central nervous system, to medicaments comprising such compounds as active ingredients, to the use of such compounds in the treatment of diseases in the central nervous system, and to methods of treatment comprising administration of such compounds.

This application is a continuation of U.S. patent application Ser. No.13/924,849, filed Jun. 24, 2013 as a continuation of U.S. patentapplication Ser. No. 13/527,364, filed Jun. 19, 2012 and issued as U.S.Pat. No. 8,575,174 on Nov. 5, 2013, which claims priority to U.S.Provisional Application Nos. 61/498,651, filed on Jun. 20, 2011, and61/537,103, filed on Sep. 21, 2011, the entirety of each of which isincorporated herein by reference.

All patents, patent applications and publications cited herein arehereby incorporated by reference in their entirety. The disclosures ofthese publications in their entireties are hereby incorporated byreference into this application in order to more fully describe thestate of the art as known to those skilled therein as of the date of theinvention described and claimed herein.

FIELD OF THE INVENTION

The present invention relates to deuterated1-piperazino-3-phenyl-indanes and salts thereof with activity atdopamine D₁ and D₂ receptors as well as the serotonin 5HT₂ receptors inthe central nervous system, to medicaments comprising such compounds asactive ingredients, and to the use of such compounds in the treatment ofdiseases in the central nervous system.

BACKGROUND OF THE INVENTION

Throughout this application, various publications are referenced infull. The disclosures of these publications are hereby incorporated byreference into this application to describe more fully the state of theart to which this invention pertains.

4-((1R,3S)-6-Chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine andsalts thereof, pharmaceutical compositions containing these salts andthe medical use thereof, including treatment of schizophrenia or otherdiseases involving psychotic symptoms, are disclosed in WO2005/016900.4-((1R,3S)-6-Chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine hasthe general formula (X), hereinafter referred to as Compound (X)

EP 638 073 recites a group of trans isomers of3-aryl-1-(1-piperazinyl)indanes substituted in the 2- and/or 3-positionof the piperazine ring. The compounds are described as having highaffinity for dopamine D₁ and D₂ receptors and the 5-HT₂ receptors andare suggested to be useful for treatment of several diseases in thecentral nervous system, including schizophrenia.

The enantiomer of formula (X) above has been described by Bøgesø et al.in J. Med. Chem., 1995, 38, page 4380-4392, in the form of the fumaratesalt, see table 5, compound (−)-38. This publication concludes that the(−)-enantiomer of compound 38 is a potent D₁/D₂ antagonist showing someD₁ selectivity in vitro. The compound is also described as a potent5-HT₂ antagonist. It is also mentioned that the compound does not inducecatalepsy in rats.

The aetiology of schizophrenia is not known, but the dopamine hypothesisof schizophrenia (Carlsson, Am. J. Psychiatry 1978, 135, 164-173),formulated in the early 1960s, has provided a theoretical framework forunderstanding the biological mechanisms underlying this disorder. In itssimplest form, the dopamine hypothesis states that schizophrenia isassociated with a hyperdopaminergic state, a notion which is supportedby the fact that all antipsychotic drugs on the market today exert somedopamine D₂ receptor antagonism (Seeman Science and Medicine 1995, 2,28-37). However, whereas it is generally accepted that antagonism ofdopamine D₂ receptors in the limbic regions of the brain plays a keyrole in the treatment of positive symptoms of schizophrenia, theblockade of D₂ receptors in striatal regions of the brain causesextrapyramidal symptoms (EPS). As described in EP 638 073 a profile ofmixed dopamine D₁/D₂ receptor inhibition has been observed with someso-called “atypical” antipsychotic compounds, in particular withclozapine(8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine),used in treatment of schizophrenic patients.

Further, selective D₁ antagonists have been connected to treatment ofsleep disorders and alcohol abuse (D. N. Eder, Current Opinion inInvestigational Drugs, 2002 3(2):284-288).

Dopamine may also play an important role in the aetiology of affectivedisorders (P. Willner, Brain. Res. Rev. 1983, 6, 211-224, 225-236 and237-246; Bøgesø et al, J. Med. Chem., 1985, 28, 1817-1828).

In EP 638 073 is described how compounds having affinity for 5-HT₂receptors, in particular 5-HT_(2A) receptor antagonists, have beensuggested for treatment of different diseases, such as schizophreniaincluding the negative symptoms in schizophrenic patients, depression,anxiety, sleep disturbance, migraine attacks and neuroleptic-inducedparkinsonism. 5-HT_(2A) receptor antagonism has also been suggested toreduce the incidence of extrapyramidal side effects induced by classicalneuroleptics (Balsara et al. Psychopharmacology 1979, 62, 67-69).

An isotopic substitution of one or more hydrogen atoms (H) by deuteriumatoms (D) in a compound may give rise to a kinetic isotope effect whichmay influence the reaction rate, e.g. metabolism of the compound. Thisis particularly the case when the isotopic replacement is in a chemicalbond that is broken or formed in a rate limiting step. In such a case,the change is termed a primary isotope effect. When the isotopicsubstitution(s) are not involved in one or more bonds that are broken asmaller rate change, termed the secondary isotope effect may beobserved.

SUMMARY OF THE INVENTION

The present invention provides compounds wherein one or more hydrogenatoms atoms (H) in one or more of the metabolic sites M1, M2 and M3 ofCompound (X) have been substituted by deuterium atoms (D).

In one aspect, the invention provides a compound of formula Y:

wherein, R¹-R¹⁰ are independently hydrogen or deuterium, and wherein atleast one of R¹-R¹⁰ comprises at least about 50% deuterium, or apharmaceutically acceptable acid addition salt thereof.

In another aspect, the invention provides pharmaceutical compositionscomprising a compound of formula (Y) and one or more pharmaceuticallyacceptable carriers, diluents, or excipients.

In another aspect, the invention provides for uses of a compound offormula (Y) or a pharmaceutical composition comprising a compound offormula (Y) in the treatment of psychosis, other diseases involvingpsychotic symptoms, psychotic disorders or diseases that present withpsychotic symptoms.

In yet another aspect, the invention provides for the manufacture of amedicament comprising a compound of formula (Y) for treatment ofpsychosis, other diseases involving psychotic symptoms, psychoticdisorders or diseases that present with psychotic symptoms.

In still another aspect, the invention provides for methods of treatingpsychosis, other diseases involving psychotic symptoms, psychoticdisorders or diseases that present with psychotic symptoms comprisingadministration of an effective amount of a compound of formula (Y) or apharmaceutically composition comprising a compound of formula (Y) to asubject in need thereof.

In still another aspect, the invention provides a compound of formula

In still another aspect, the invention provides a process for thepreparation of compound

(S)-(XV) comprising treating compound (XIV) with [(S)-BINAP]Rh(I)BF₄.

In still another aspect, the invention provides a process for thepreparation of compound (1R,3S)-(IV) tartrate comprising, treatment ofracemic trans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-1(d₃),2,2-trimethyl-piperazine with L-(+)-tartaric acid.

Still other objects and advantages of the invention will become apparentto those of skill in the art from the disclosure herein, which is simplyillustrative and not restrictive. Thus, other embodiments will berecognized by the skilled artisan without departing from the spirit andscope of the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows major metabolic sites of Compound (X).

FIG. 2 shows Compound (I) and Compound (XI), each as the(1R,3S)-enantiomer.

FIGS. 3A-3B show NMR spectra of Compound (II) and Compound (V). Selectedregions of the proton-decoupled and proton- and deuterium-decoupled ¹³CNMR spectra of Compound (II) [FIG. 3A] and Compound (V) [FIG. 3B] areshown.

FIG. 4 shows the mass spectrum of Compound (IV).

FIG. 5 shows formation of the metabolite Compound (XI) by metabolism ofCompound (X) and Compound (I) (0.1 microM) in cryopreserved doghepatocytes (n=2 the bars represent max and min results).

FIG. 6 shows formation of the metabolite Compound (XI) by metabolism ofCompound (X) and Compound (I) (1 microM) in cryopreserved doghepatocytes (n=2 the bars represent max and min results).

FIG. 7 shows formation of the desmethyl metabolite by metabolism ofCompound (II), (IV) and (X) (1 micro M) in human liver microsomes (n=3,the bars represent standard deviation).

FIG. 8 shows formation of the desmethyl metabolite by metabolism ofCompound (II), (IV) and (X) (10 micro M) in human liver microsomes (n=3,the bars represent standard deviation).

FIG. 9 shows formation of the desmethyl metabolite by metabolism ofCompound (III) (10 micro M) in human liver microsomes (n=3, the barsrepresent standard deviation).

FIG. 10 shows formation of the desmethyl metabolite by metabolism ofCompound (V) (10 micro M) in human liver microsomes (n=3, the barsrepresent standard deviation).

FIG. 11 shows formation of the desmethyl metabolite by metabolism ofCompound (VI) (10 micro M) in human liver microsomes (n=3, the barsrepresent standard deviation).

FIG. 12 shows formation of the desmethyl metabolite by metabolism ofCompound (VII) (10 micro M) in human liver microsomes (n=3, the barsrepresent standard deviation).

FIG. 13 shows the chemical structure of compounds (I)-(VII), (X)-(XI),and (XIX)-(XXI).

FIG. 14 shows formation of the desmethyl metabolite by metabolism ofCompound (II) and (X) (10 micro M) by recombinant human liver CYP2C19(n=3, the standard deviation).

FIG. 15 shows formation of the desmethyl metabolite by metabolism ofCompound (IV) and Compound (X) (1 micro M) by recombinant human liverCYP2C19 (n=3, the bars represent standard deviation).

FIG. 16 shows PCP-induced hyperactivity in mice for compound (IV).

FIG. 17 shows cataleptic response in rats for compound (IV).

FIG. 18 shows X-ray diffractograms on two batches of hydrogen tartratesalt of Compound (IV).

DETAILED DESCRIPTION OF THE INVENTION

Atypical antipsychotics have been the subject of numerous studies by thepharmaceutical industry, and have shown promise in treating mentaldisorders such as schizophrenia, bipolar disorder, dementia, anxietydisorder and obsessive-compulsive disorder (OCD). The mechanism ofaction of these agents remains unknown; however all antipsychotics workto some degree on the dopamine system. Most atypical antipsychoticsexhibit activity at dopamine subtype receptors 1 and 2 (D₁ and D₂,respectively), and at the serotonin receptors subtype 2 (5-HT₂). In somecases, the “atypical” designation was assigned to antipsychotics thatdid not induce extrapyramidal side effects; however it has been shownthat some atypical antipsychotics still induce extrapyramidal sideeffects, albeit to a lesser degree that that observed with typicalantipsychotics (Weiden, P. J., “EPS profiles: the atypicalantipsychotics are not all the same” J. Psychiatr. Pract. 2007, 13(1):13-24; herein incorporated by reference in its entirety). Approvedatypical antipsychotics include, for example, amisulpride (Solian),aripiprazole (Abilify), asenapine (Saphris), blonanserin (Lonasen),clotiapine (Entumine), clozapine (Clozaril), iloperidone (Fanapt),lurasidone (Latuda), mosapramine (Cremin), olanzapine (Zyprexa),paliperidone (Invega), perospirone (Lullan), quetiapine (Seroquel),remoxipride (Roxiam), risperidone (Risperdal), sertindole (Serdolect),supliride (Sulpirid, Eglonyl), ziprasidone (Geodon, Zeldox), andzotepine (Nipolept). Several others are currently under development.Because the mechanism of atypical antipsychotics is not well understood,side effects associated with these drugs have been difficult to designaround. Thus, there is a need for additional antipsychotic therapieswith potential for reduced side effect and/or improved therapeuticprofile relative to existing therapies.

In one aspect, the present invention provides compounds wherein one ormore hydrogen atoms (H) in one or more of the metabolic sites M1, M2 andM3 of Compound (X) have been substituted by deuterium atoms (D).Compound (X) and variants thereof are described in, for example U.S.Pat. Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240; 8,076,342; U.S.Patent Publication Nos. 2008/0269248; 2010/0069676; 2011/0178094;2011/0207744; WO 2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38,4380-4392; each herein incorporated by reference in its entirety.

The kinetic isotope effect may potentially influence the rate ofmetabolism at one or more of the metabolic sites M1, M2, and M3indicated in FIG. 1. The inventors of the present invention haveidentified three major metabolic sites of4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine(Compound (X)) denoted herein as M1, M2 and M3 and indicated in FIG. 1.

Deuteration of a compound at a site subject to oxidative metabolism may,in some cases reduce the rate of metabolism for a compound due to theprimary isotope effect. If the C—H bond cleavage step is rate limiting,a significant isotope effect may be observed. However, if other stepsdrive the rate of metabolism for a compound, the C—H bond cleavage stepis not rate limiting and the isotope effect may be of littlesignificance. Additionally, a negative isotope effect can be observedwhere reaction rate is increased upon substitution with deuterium. Thus,incorporation of deuterium at a site subject to oxidative enzymaticmetabolism does not predictably impact pharmacokinetics (See, forexample, U.S. Pat. No. 7,678,914; Drug Metab. Dispos. 1986, 14, 509;Arch. Toxicol. 1990, 64, 109; Int. Arch. Occup. Environ. Health 1993,65(Suppl. 1): S139; each herein incorporated by reference in itsentirety). The impact of deuterium incorporation is unpredictable doesnot work for many drugs or classes of drugs. Decreased metabolicclearance has been observed with some deuterated compounds relative tonon-deuterated derivatives; whereas metabolism of other compounds hasbeen unimpacted. Examples of studies indicating lack of predictabilityregarding deuterium incorporation include U.S. Pat. No. 6,221,335; J.Pharm. Sci. 1975, 64, 367-391; Adv. Drug. Res. 1985, 14, 1-40; J. Med.Chem. 1991, 34, 2871-2876; Can. J. Physiol. Pharmacol. 1999, 79-88;Silverman, R. B., The Organic Chemistry of Drug Design and Drug Action,2^(nd) Ed. (2004), 422; Curr. Opin. Drug Dev. 2006, 9, 101-109; ChemicalRes. Tox. 2008, 1672; Harbeson, S. L and Tung, R. D. “Deuterium in DrugDiscovery and Development,” in Ann. Rep. Med. Chem. 2011, 46, 404-418;each herein incorporated by reference in its entirety. Evenincorporation deuterium at known sites of metabolism has anunpredictable impact on metabolic profile. Metabolic switching mayresult wherein the metabolic profile of a particular drug is changed dueto deuterium incorporation, thus leading to different proportions of (ordifferent) metabolites than observed with a non-deuterated analog of thesame drug. The new metabolic profile may result in a distincttoxicological profile of the deuterated analog. Adding to the potentialcomplications of deuterium incorporation is the possibility ofdeuterium/hydrogen exchange in the physiological environment (Adv. Drug.Res. 1985, 14, 1-40; herein incorporated by reference in its entirety).

In some embodiments, isotopic substitution of one or more hydrogen atomsin Compound (X) by deuterium atoms has given rise to a kinetic isotopeeffect that influences the rate of metabolism.

The isotopic substitution of hydrogen atoms in Compound (X) by deuteriumatoms results in less metabolism of the deuterated compound as shown tooccur in dog hepatocytes where for instance an approximately 50%decrease in formation of the desmethyl metabolite (Compound (XI)) fromCompound (I) (FIG. 2) was noted in comparison to the formation ofCompound (XI) from the metabolism of Compound (X).

Deuteration of the free phenyl, optionally in combination withdeuteration of the 1-methyl group (Compound (II) and (IV)), surprisinglyreduces the amount of the desmethyl metabolite produced in human livermicrosomes as compared to the non-deuterated compound (Compound (X)).Also surprisingly, deuteration of the 1-methyl group impacted metabolismin dog but not human hepatocytes, thus indicative of theunpredictability of deuteration on pharmacological properties.

The effect of the reduced metabolism is higher bioavailability of thedeuterated, parent compound and less metabolite formation. Without beingbound by theory, based on the results described in the experimentalsection of this application the same effect is expected to show up aftermultiple dosing in humans, allowing for lower doses to be administeredto humans i.e. less burden to the entire body, e.g. the liver, and aless frequent dosing.

The desmethyl metabolite (Compound (XI)) is known to have hERG affinityand thus potentially contribute to QTc prolongation. As mentioned above,deuteration of the free phenyl optionally in combination withdeuteration of the 1-methyl group (Compound (II) and (IV)), surprisinglyreduces the amount of the desmethyl metabolite produced in human livermicrosomes as compared to the non-deuterated compound (Compound (X)).Accordingly and without being bound by theory, it is anticipated thatthere will be less interaction with the hERG channel and resultant lowerburden on the heart when dosing the deuterated variants of Compound (X)[e.g., compounds of formula (Y)] compared to when dosing Compound (X).

The invention is further detailed in the exemplary embodiments providedherein.

DEFINITIONS

The term “compound(s) of the invention” as used herein means Compounds(Y), (I), (II), (III), (IV), (V), (VI), and/or (VII), and may includesalts, hydrates and/or solvates thereof. The compounds of the presentinvention are prepared in different forms, such as salts, hydrates,and/or solvates, and the invention includes compositions and methodsencompassing all variant forms of the compounds.

The term “composition(s) of the invention” as used herein meanscompositions comprising Compounds (Y), (I), (II), (III), (IV), (V),(VI), and/or (VII), or salts, hydrates, and solvates thereof. Thecompositions of the invention may further comprise one or more chemicalcomponents such as, for example, excipients, diluents, vehicles orcarriers.

The term “method(s) of the invention” as used herein means methodscomprising treatment with the compounds and/or compositions of theinvention.

As used herein the term “about” is used herein to mean approximately,roughly, around, or in the region of. When the term “about” is used inconjunction with a numerical range, it modifies that range by extendingthe boundaries above and below the numerical values set forth. Ingeneral, the term “about” is used herein to modify a numerical valueabove and below the stated value by a variance of 20 percent up or down(higher or lower).

An “effective amount”, “sufficient amount” or “therapeutically effectiveamount” as used herein is an amount of a compound that is sufficient toeffect beneficial or desired results, including clinical results. Assuch, the effective amount may be sufficient, for example, to reduce orameliorate the severity and/or duration of an affliction or condition,or one or more symptoms thereof, prevent the advancement of conditionsrelated to an affliction or condition, prevent the recurrence,development, or onset of one or more symptoms associated with anaffliction or condition, or enhance or otherwise improve theprophylactic or therapeutic effect(s) of another therapy. An effectiveamount also includes the amount of the compound that avoids orsubstantially attenuates undesirable side effects.

As used herein and as well understood in the art, “treatment” is anapproach for obtaining beneficial or desired results, including clinicalresults. Beneficial or desired clinical results may include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions, diminution of extent of disease, a stabilized (i.e., notworsening) state of disease, preventing spread of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.

The term “in need thereof” refers to the need for symptomatic orasymptomatic relief from a condition such as, for example, psychosis ora psychotic disorder. The subject in need thereof may or may not beundergoing treatment for conditions related to, for example, psychosisor a psychotic disorder.

The term “carrier” refers to a diluent, adjuvant, excipient, or vehiclewith which a compound is administered. Non-limiting examples of suchpharmaceutical carriers include liquids, such as water and oils,including those of petroleum, animal, vegetable or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical carriers may also be saline, gum acacia, gelatin,starch paste, talc, keratin, colloidal silica, urea, and the like. Inaddition, auxiliary, stabilizing, thickening, lubricating and coloringagents may be used. Other examples of suitable pharmaceutical carriersare described in Remington: The Science and Practice of Pharmacy,21^(st) Edition (University of the Sciences in Philadelphia, ed.,Lippincott Williams & Wilkins 2005). (hereby incorporated by referencein its entirety).

The terms “animal,” “subject” and “patient” as used herein include allmembers of the animal kingdom including, but not limited to, mammals,animals (e.g., cats, dogs, horses, swine, etc.) and humans.

The term “isotopic variant” as used herein means a compound obtained bysubstituting one or more hydrogen in a parent compound not comprisingdeuterium atoms by deuterium atoms.

It is recognized that elements are present in natural isotopicabundances in most synthetic compounds, and result in inherentincorporation of deuterium. However, the natural isotopic abundance ofhydrogen isotopes such as deuterium is immaterial (about 0.015%)relative to the degree of stable isotopic substitution of compoundsindicated herein. Thus, as used herein, designation of an atom asdeuterium at a position indicates that the abundance of deuterium issignificantly greater than the natural abundance of deuterium. Any atomnot designated as a particular isotope is intended to represent anystable isotope of that atom, as will be apparent to the ordinarilyskilled artisan.

Compounds (Y) are isotopic variants of Compound (X).

In some embodiments, compounds (I), (II), (III), (IV), (V), (VI) and(VII) are isotopic variants of Compound (X).

M1 is a site of Compound (X) susceptible to metabolism; M1 consists of—CH₂— in the 6-position of the piperazine of Compound (X).

M2 is a site of compound (X) susceptible to metabolism; M2 consists ofthe N-bound methyl of the piperazine of Compound (X).

M3 is a site of Compound (X) susceptible to metabolism; M3 consists ofthe phenyl group of Compound (X).

Parent compound is the chemical compound which is the basis for itsderivatives obtained either by substitution or breakdown, e.g. metabolicbreakdown. In the context of the present invention the parent compoundis the Active Pharmaceutical Ingredient (API).

In some embodiments, any atom not designated as deuterium is present atits natural isotopic abundance. In some embodiments, any hydrogen atomnot designated as deuterium is present at less than 1% isotopicabundance of deuterium.

In one aspect, the invention provides a compound of formula (Y):

wherein, R¹-R¹⁰ are independently hydrogen or deuterium, wherein atleast one of R¹-R¹⁰ comprises at least about 50% deuterium, or apharmaceutically acceptable acid addition salt thereof.

In another aspect, the invention provides pharmaceutical compositionscomprising a compound of formula (Y) and one or more pharmaceuticallyacceptable carriers, diluents, or excipients.

In another aspect, the invention provides for uses of a compound offormula (Y) or a pharmaceutical composition comprising a compound offormula (Y) in the treatment of psychosis, other diseases involvingpsychotic symptoms, psychotic disorders or diseases that present withpsychotic symptoms.

In yet another aspect, the invention provides for the manufacture of amedicament comprising a compound of formula (Y) for treatment ofpsychosis, other diseases involving psychotic symptoms, psychoticdisorders or diseases that present with psychotic symptoms.

In still another aspect, the invention provides for methods of treatingpsychosis, other diseases involving psychotic symptoms, psychoticdisorders or diseases that present with psychotic symptoms comprisingadministration of an effective amount of a compound of formula (Y) or apharmaceutically composition comprising a compound of formula (Y).

In some embodiments, the compound is racemic. In some embodiments, thecompound is enantiomerically enriched.

In some embodiments, the compound is selected from the group consistingof

In some embodiments, R¹ and R² comprise deuterium, R³-R⁵ comprisedeuterium, or R⁶-R¹⁰ comprise deuterium.

In some embodiments, R¹ and R² comprise deuterium. In some embodiments,R¹ and R² comprise deuterium and R³-R⁵ comprise hydrogen.

In some embodiments, R³-R⁵ comprise deuterium. In some embodiments,R³-R⁵ comprise hydrogen.

In some embodiments, R⁶-R¹⁰ comprise deuterium. In some embodiments,R⁶-R¹⁰ comprise deuterium and R³-R⁵ comprise hydrogen.

In some embodiments, R¹-R⁵ comprise deuterium.

In some embodiments, R¹, R², and R⁶-R¹⁰ comprise deuterium.

In some embodiments, R³-R¹⁰ comprise deuterium.

In some embodiments, R¹-R¹⁰ comprise deuterium.

In some embodiments, the compound is

In some embodiments, the compound is

In some embodiments, the compound is

In some embodiments, the compound is

In some embodiments, the compound is

In some embodiments, the compound is

In some embodiments, the compound is

In some embodiments, at least about 75% of the compound has a deuteriumatom at each position designated as deuterium, and any atom notdesignated as deuterium is present at about its natural isotopicabundance.

In some embodiments, at least about 85% of the compound has a deuteriumatom at each position designated as deuterium, and any atom notdesignated as deuterium is present at about its natural isotopicabundance.

In some embodiments, at least about 90% of the compound has a deuteriumatom at each position designated as deuterium, and any atom notdesignated as deuterium is present at about its natural isotopicabundance.

In some embodiments, the compound is a salt selected from the groupconsisting of fumarate, maleate, succinate, and tartrate. In someembodiments, the compound is a fumarate salt. In some embodiments, thecompound is a hydrogen fumarate salt. In some embodiments, the compoundis a maleate salt. In some embodiments, the compound is a hydrogenmaleate salt. In some embodiments, the compound is a succinate salt. Insome embodiments, the compound is a hydrogen succinate salt. In someembodiments, the compound is a tartrate salt. In some embodiments, thecompound is the hydrogen tartrate salt.

In some embodiments, the compound is the hydrogen tartrate salt of(1R,3S)-(IV).

In some embodiments, the psychosis or disease involving psychoticsymptoms is schizophrenia, schizophreniform disorder, schizoaffectivedisorder, delusional disorder, brief psychotic disorder, sharedpsychotic disorder, bipolar disorder, or mania in bipolar disorder. Insome embodiments, the psychosis or disease involving psychotic symptomsis schizophrenia.

In some embodiments, the methods further comprise administration of withone or more neuroleptic agents.

In some embodiments, the uses further comprise use of a one or moreneuroleptic agents.

In some embodiments, the neuroleptic agent is selected from the groupconsisting of sertindole, olanzapine, risperidone, quetiapine,aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

In some embodiments, administration is oral, sublingual, or buccal. Insome embodiments, administration is oral.

In some embodiments, the subject is a mammal. In some embodiments, thesubject is a rodent, cat, dog, monkey, horse, swine, bovine, or human.In some embodiments, the subject is a rodent, cat, dog, monkey, bovineor human. In some embodiments, the subject is a mouse, rat, cat, dog,monkey, or human. In some embodiments, the subject is a mouse, rat, dog,monkey, or human. In some embodiments, the subject is a mouse, rat, dog,or human. In some embodiments, the subject is a mouse, rat or a human.In some embodiments, the subject is a dog or a human. In someembodiments, the subject is a human.

In some embodiments, designation of a position as “D” in a compound hasa minimum deuterium incorporation of greater than about 40% at thatposition. In some embodiments, designation of a position as “D” in acompound has a minimum deuterium incorporation of greater than about 50%at that position. In some embodiments, designation of a position as “D”in a compound has a minimum deuterium incorporation of greater thanabout 60% at that position. In some embodiments, designation of aposition as “D” in a compound has a minimum deuterium incorporation ofgreater than about 65% at that position. In some embodiments,designation of a position as “D” in a compound has a minimum deuteriumincorporation of greater than about 70% at that position. In someembodiments, designation of a position as “D” in a compound has aminimum deuterium incorporation of greater than about 75% at thatposition. In some embodiments, designation of a position as “D” in acompound has a minimum deuterium incorporation of greater than about 80%at that position. In some embodiments, designation of a position as “D”in a compound has a minimum deuterium incorporation of greater thanabout 85% at that position. In some embodiments, designation of aposition as “D” in a compound has a minimum deuterium incorporation ofgreater than about 90% at that position. In some embodiments,designation of a position as “D” in a compound has a minimum deuteriumincorporation of greater than about 95% at that position. In someembodiments, designation of a position as “D” in a compound has aminimum deuterium incorporation of greater than about 97% at thatposition. In some embodiments, designation of a position as “D” in acompound has a minimum deuterium incorporation of greater than about 99%at that position.

Pharmaceutically Acceptable Salts

The present invention also comprises salts of the compounds, typically,pharmaceutically acceptable salts. Such salts include pharmaceuticallyacceptable acid addition salts. Acid addition salts include salts ofinorganic acids as well as organic acids.

Representative examples of suitable inorganic acids includehydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic,nitric acids and the like. Representative examples of suitable organicacids include formic, acetic, trichloroacetic, trifluoroacetic,propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic,lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic,picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic,tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic,gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids,theophylline acetic acids, as well as the 8-halotheophyllines, forexample 8-bromotheophylline and the like. Further examples ofpharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in Berge, S. M. etal., J. Pharm. Sci. 1977, 66, 2, and Gould, P. L., Int. J. Pharmaceutics1986, 33, 201-217; the contents of each are hereby incorporated byreference.

Furthermore, the compounds of this invention may exist in unsolvated aswell as in solvated forms with pharmaceutically acceptable solvents suchas water, ethanol and the like. In general, the solvated forms areconsidered comparable to the unsolvated forms for the purposes of thisinvention.

Headings and sub-headings are used herein for convenience only, andshould not be construed as limiting the invention in any way.

The use of any and all examples, or exemplary language (including “forinstance”, “for example”, “e.g.”, and “as such”) in the presentspecification is intended merely to better illuminate the invention, anddoes not pose a limitation on the scope of invention unless otherwiseindicated.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context.

Unless otherwise indicated, all exact values provided herein arerepresentative of corresponding approximate values (e.g., all exactexemplary values provided with respect to a particular factor ormeasurement can be considered to also provide a correspondingapproximate measurement, modified by “about,” where appropriate).

The description herein of any aspect or aspect of the invention usingterms such as “comprising”, “having,” “including,” or “containing” withreference to an element or elements is intended to provide support for asimilar aspect or aspect of the invention that “consists of”, “consistsessentially of”, or “substantially comprises” that particular element orelements, unless otherwise stated or clearly contradicted by context.

Exemplary syntheses of the compounds of the invention can be readilyachieved by methods described, for example, U.S. Pat. Nos. 5,807,855;7,648,991; 7,767,683; 7,772,240; 8,076,342; U.S. Patent Publication Nos.2008/0269248; 2010/0069676; 2011/0178094; 2011/0207744; WO 2005/016900;EP 0 638 073; and J. Med. Chem. 1995, 38, 4380-4392; each hereinincorporated by reference in its entirety. Such methods, and similarmethods can be performed using deuterated reagents and/or intermediates,and/or introducing deuterium atoms to a chemical structure according toprotocols known in the art.

Further exemplary methods of synthesis include conversion of indanone Ato intermediate C via treatment of 3-bromo-6-chloro-indan-1-one (A; forreferences on this material, see: Bøgesø EP 35363 A1 19810909 andKehler, Juhl, Püschl, WO 2008025361; each herein incorporated byreference in its entirety) with a base such as triethylamine in asolvent such as tetrahydrofuran at ambient temperature (Scheme 1).Removal of the precipitated amine hydrobromide salt by filtration andconcentration of the filtrate will afford 6-chloro-inden-1-one (B). Thismaterial can be reacted with phenyl-d₅-boronic acid in the presence ofapproximately 1 equivalent of a base such as triethylamine and acatalytic amount of a 1:1 mixture of [Rh(ndb)₂]BF₄(bis(norbornadiene)rhodium(I) tetrafluoroborate) and racemic BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) in a suitable solvent(e.g. approximately 10:1 solvent mixture of 1,4-dioxane and water) underan atmosphere of argon at elevated temperature (e.g. about 100° C.).Work-up will afford racemic 6-chloro-3-phenyl-d₅-indan-1-one (C).

Treatment of 6-chloro-3-phenyl-d₅-indan-1-one (C) with a reductive basesuch as sodium borohydride (˜2 equivalents) in a ˜10:1 solvent mixtureof tetrahydrofuran and water at low temperature (approximately −15° C.)will lead to reduction of the carbonyl group to the correspondingalcohol (Scheme 2). Work-up will afford racemiccis-6-chloro-3-phenyl-indan-1-ol (D). Treatment of this material withvinyl butyrate (approximately 5 equivalents) and Novozym 435® in asolvent such as di-iso-propyl ether at ambient temperature will afford(1S,3S)-6-chloro-3-phenyl-indan-1-ol (E) after work-up.

Alternatively, performing the sequence from A to E using phenyl boronicacid or 4,4,5,5-tetramethyl-2-phenyl-[1,3,2]dioxaborolane instead of4,4,5,5-tetramethyl-2-d₅-phenyl-[1,3,2]dioxaborolane will lead to(1S,3S)-6-chloro-3-phenyl-indan-1-ol (E′) (Scheme 3).

Further alternative synthetic methods to obtain E′ are disclosed in thepatent literature (Dahl, Wøhlk Nielsen, Suteu, Robin, BrøsenWO2006/086984 A1; Bang-Andersen, Bøgesø, Jensen, Svane, Dahl, Howells,Lyngsø, Mow WO2005/016901 A1; each herein incorporated by reference inits entirety). These procedures rely on benzyl cyanide as one of thesubstrates. Using benzyl cyanide-d₇ (commercially available fromAldrich, catalog #495840) or phenyl-d₅-acetonitrile (commerciallyavailable from Aldrich catalog #495859 or from CDN catalog # D-5340 orfrom Kanto catalog #49132-27) the same procedure may lead to E (Scheme4). As alternatives to the commercial sources, benzyl cyanide-d₇ andphenyl-d₅-acetonitrile can be prepared sodium cyanide and benzyl-d₇chloride (commercially available from Aldrich, catalog #217336) andbenzyl-2,3,4,5,6-d₅ chloride (commercially available from Aldrich,catalog #485764), respectively.

Treatment of E with approximately 4 equivalents ofdi-iso-propylethylamine and approximately 2 equivalents methanesulphonicanhydride in tetrahydrofuran at approximately −18° C. followed by slowheating to approximately −5° C. and subsequent treatment withapproximately 4 equivalents 2,2-dimethyl-piperazine will lead to theformation of1-((1R,3S)-6-chloro-3-phenyl-d₅-indan-1-yl)-3,3-dimethyl-piperazine (F)that can be purified after the reaction (Scheme 5). Alternatively, onecan convert alcohol E to the corresponding chloride, predominantly withretention of configuration at C1 leading to(1S,3S)-1-chloro-3-d₅-phenyl-indan (E″; similarly E′ can be converted to(1S,3S)-1-chloro-3-phenyl-indan (E′″)). Chloride E″ can be reacted with2,2-dimethyl-piperazine to afford F. The final step can be performed asdescribed for the preparation of Compound (I).butanedioic acid salt bythe use of iodomethane to give Compound (II) or d₃-iodomethane to giveCompound (IV), respectively. Alternatively, as described below, themethyl group or d₃-methyl group can be installed by refluxing inHCHO/HCOOH or DCDO/DCOOD, respectively.

(2-Amino-2-methyl-propyl)-carbamic acid tert-butyl ester (G) can beprepared from 2-methyl-propane-1,2-diamine and di-tert-butyl dicarbonate(alternatively, G is claimed to be commercially available: Prime catalog# POI-1362-MB4; Rovathin catalog # NX45401). Reaction of G with ahaloacetyl halide such as either chloroacetyl chloride or bromoacetylbromide will give [2-(2-chloro-acetylamino)-2-methyl-propyl]-carbamicacid tert-butyl ester or[2-(2-bromo-acetylamino)-2-methyl-propyl]-carbamic acid tert-butyl ester(H), respectively (Scheme 6). Treatment of either variant of H with acidfollowed by base will lead to the formation of6,6-dimethyl-piperazine-2-one (I). This material can be reduced to2,2-dimethyl-5,5-d₂-piperazine (J) by treatment with lithium aluminiumdeuteride.

Alternatively, J can be prepared from 2-amino-2-methyl-propionic acid.Reaction of 2-amino-2-methyl-propionic acid and di-tert-butyldicarbonate will afford 2-tert-butoxycarbonylamino-2-methyl-propionicacid (K) (Scheme 7). The acid functionality can be converted to thecorresponding Weinreb amide by reaction with O,N-dimethyl-hydroxylaminein the presence of a suitable coupling reagent such as2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium (HATU) or1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) to afford[1-(methoxy-methyl-carbamoyl)-1-methyl-ethyl]-carbamic acid tert-butylester (L). Selective reduction of the Weinreb amide leads to(1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (M). Reductiveamination involving aldehyde M and amino-acetic acid methyl ester can beused to prepare (2-tert-butoxycarbonylamino-2-methyl-propylamino)-aceticacid methyl ester (N). Treatment of carbamate-ester N with a suitableacid, such as trifluoroacetic acid, will lead to the formation ofpiperazinone I that upon treatment with lithium aluminium deuteridegives piperazine J.

Using J instead of 2,2-dimethyl-piperazine as described for theconversion of E to Compounds (II) and (IV) will lead to Compounds (VI)and Compound (VII), respectively. Similarly, using E′ and J instead of2,2-dimethyl-piperazine and E will lead to Compound (III) and Compound(V).

In another aspect, the invention provides a process for the preparationof compound

(S)-(XV) comprising treating compound (XIV) with [(S)-BINAP]Rh(I)BF₄.

In another aspect, the invention provides a process of the preparationof compound (1R,3S)-(IV) tartrate comprising treatment of racemictrans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-1(d₃),2,2-trimethyl-piperazine with L-(+)-tartaric acid.

In some embodiments, racemictrans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-1(d₃),2,2-trimethyl-piperazine is generated from the corresponding succinatesalt thereof.

In some embodiments, racemictrans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-1(d₃),2,2-trimethyl-piperazine succinate is generated from the maleate salt ofracemictrans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-3,3-dimethyl-piperazine.

In some embodiments, acetophenone-d₅ is converted to an enol ether. Insome embodiments, the enol ether is a silyl enol ether. In someembodiments, the enol ether of acetophenone-d₅ is converted to thecorresponding vinyl boronate. In some embodiments, the enol ether ofacetophenone-d₅ is treated with bis(pinacolato)diboron. In someembodiments, the vinyl boronate is treated with2-halo-5-chlorobenzaldehyde.

In some embodiments, the compounds exist as racemates. In someembodiments, the compounds exist in greater than about 70% enantiomericexcess. In some embodiments, the compounds exist in greater than about75% enantiomeric excess. In some embodiments, the compounds exist ingreater than about 80% enantiomeric excess. In some embodiments, thecompounds exist in greater than about 85% enantiomeric excess. In someembodiments, the compounds exist in greater than about 90% enantiomericexcess. In some embodiments, the compounds exist in greater than about92% enantiomeric excess. In some embodiments, the compounds exist ingreater than about 95% enantiomeric excess. In some embodiments, thecompounds exist in greater than about 97% enantiomeric excess. In someembodiments, the compounds exist in greater than about 99% enantiomericexcess.

Pharmaceutical Compositions

The present invention further provides pharmaceutical compositionscomprising a therapeutically effective amount of the compounds of thepresent invention and a pharmaceutically acceptable carrier or diluent.

The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers, diluents orexcipients, in either single or multiple doses. The pharmaceuticalcompositions according to the invention may be formulated withpharmaceutically acceptable carriers or diluents as well as any otherknown adjuvants and excipients in accordance with conventionaltechniques such as those disclosed in Remington: The Science andPractice of Pharmacy, 21^(st) Edition (University of the Sciences inPhiladelphia, ed., Lippincott Williams & Wilkins 2005). Furtherexemplary compositions of the compounds of the invention are describedin, for example, U.S. Pat. Nos. 5,807,855; 7,648,991; 7,767,683;7,772,240; 8,076,342; U.S. Patent Publication Nos. 2008/0269248;2010/0069676; 2011/0178094; 2011/0207744; WO 2005/016900; EP 0 638 073;and J. Med. Chem. 1995, 38, 4380-4392; each herein incorporated byreference in its entirety.

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as oral, nasal, topical(including buccal and sublingual), and parenteral (includingsubcutaneous, intramuscular, intrathecal, intravenous and intradermal)routes. It will be appreciated that the route will depend on the generalcondition and age of the subject to be treated, the nature of thecondition to be treated and the active ingredient.

The daily dose of the compounds of the invention, calculated as the freebase, is suitably from about 1.0 to about 160 mg/day, more suitably fromabout 1 to about 100 mg, e.g. preferably from about 2 to about 55, suchas from about 2 to about 15 mg, e.g. from about 3 to about 10 mg. Insome embodiments, the daily dose is from about 0.1 mg to about 500 mg.In some embodiments, the daily dose is from about 1 mg to about 500 mg.In some embodiments, the daily dose is from about 1 mg to about 400 mg.In some embodiments, the daily dose is from about 1 mg to about 300 mg.In some embodiments, the daily dose is from about 1 mg to about 200 mg.In some embodiments, the daily dose is from about 1 mg to about 160 mg.In some embodiments, the daily dose is from about 1 mg to about 100 mg.In some embodiments, the daily dose is from about 1 mg to about 60 mg.In some embodiments, the daily dose is from about 2 mg to about 30 mg.In some embodiments, the daily dose is from about 2 mg to about 15 mg.In some embodiments, the daily dose is from about 3 mg to about 10 mg.In some embodiments, the daily dose is about 60 mg. In some embodiments,the daily dose is about 50 mg. In some embodiments, the daily dose isabout 40 mg. In some embodiments, the daily dose is about 30 mg. In someembodiments, the daily dose is about 20 mg. In some embodiments, thedaily dose is about 10 mg. In some embodiments, the daily dose is about5 mg. In some embodiments, the daily dose is about 3 mg. In someembodiments, the daily dose is about 2 mg. In some embodiments, thedaily dose is about 1 mg.

For parenteral routes such as intravenous, intrathecal, intramuscularand similar administration, typical doses are in the order of half thedose employed for oral administration.

The compounds of this invention are generally utilized as the freesubstance or as a pharmaceutically acceptable salt thereof. Examples ofsuitable organic and inorganic acids are described herein.

In some embodiments, the composition comprises a cyclodextrin. In someembodiments, the composition comprises a cyclodextrin in water. In someembodiments, the cyclodextrin is hydroxypropyl-β-cyclodextrin. In someembodiments, the composition comprises hydroxypropyl-β-cyclodextrin inwater.

Treatment of Disorders

The invention also relates to the medical use of compounds of thepresent invention, such as for the treatment of a disease in the centralnervous system, including psychosis, in particular schizophrenia orother diseases involving psychotic symptoms, such as, e.g.,Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder,Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorderas well other psychotic disorders or diseases that present withpsychotic symptoms, e.g. bipolar disorder, such as mania in bipolardisorder. Compounds and/or compositions of the invention can further beused in treatment of disorders such as those described in, for example,U.S. Pat. Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240; 8,076,342;U.S. Patent Publication Nos. 2008/0269248; 2010/0069676; 2011/0178094;2011/0207744; WO 2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38,4380-4392; each herein incorporated by reference in its entirety. Theinvention also relates to the medical use of compounds of the presentinvention as combination therapy in conjunction with other therapeuticagents such as those described in, for example, U.S. Pat. Nos.5,807,855; 7,648,991; 7,767,683; 7,772,240; 8,076,342; U.S. PatentPublication Nos. 2008/0269248; 2010/0069676; 2011/0178094; 2011/0207744;WO 2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38, 4380-4392;each herein incorporated by reference in its entirety.

It will recognized that one or more features of any embodimentsdisclosed herein may be combined and/or rearranged within the scope ofthe invention to produce further embodiments that are also within thescope of the invention.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be within the scope of the present invention.

The invention is further described by the following non-limitingExamples.

EXAMPLES

Examples are provided below to facilitate a more complete understandingof the invention. The following examples illustrate the exemplary modesof making and practicing the invention. However, the scope of theinvention is not limited to specific embodiments disclosed in theseExamples, which are for purposes of illustration only, since alternativemethods can be utilized to obtain similar results.

Purification of compounds by chromatography refers to the application ofsilica gel chromatography using either manual flash chromatography orautomated flash chromatography, typically performed using eluentgradients from heptanes to ethyl acetate or mixtures of ethyl acetate,triethylamine and methanol.

Description of LCMS Methods

Compounds (I), (II), (III), (IV), (V), (VI) and (VII) were characterizedby LCMS using the following methods (Table 1):

TABLE 1 Methods for LCMS Analysis Methods WXV-AB5, WXV-AB10, andWXV-AB30 Equipment Agilent 1100 LCMS system with ELS Detector [methodWuXiAB25 Agilent 1200 LCMS system with ELS Detector] Pump G1311ADegasser G1379A Well-plate Autosampler G1367A Column Oven G1316A DADG1315B MSD G1946C or G1956A [method WuXiAB25 6110] ELSD Alltech ELSD 800[method WuXiAB25 Aligent 1200] Column YMC ODS-AQ [method WuXiAB25Agilent TC-C18] Particle size 5 micrometer Pore size 12 nm Dimension50 * 2.0 mm ID [method WuXiAB25 50 * 2.1 mm ID] Injection volume 2microL Column temperature 50° C. Flow 0.8 mL/min Mobile phases A 0.1%TFA in water B 0.05% TFA in acetonitrile Total run time 4.5 min Gradientlinear UV Detection Wavelength 254 nm ELSD Detection Temperature: 50° C.Gas Pressure: 3.2 bar Time Gradient WXV-ABO5   0 min 95% A 5% B  3.5 min0% A 100% B 3.55 min 95% A 6% B WXV-AB10   0 min 90% A 10% B  3.4 min100% B  3.5 min 100% B 3.51 min 90% A 10% B WXV-AB30   0 min 70% A 30% B 3.2 min 0% A 100% B  3.5 min 0% A 100% B 3.55 min 70% A 30% B WuXiAB25  0 min 75% A 25% B  3.4 min 0% A 100% B   4 min 0% A 100% B 4.01 min75% A 25% B  4.5 min 75% A 25% B Method 131 Equipment Sciex API150EXequipped with APPI-source operating in positive ion mode LC-MS were runon a Sciex API150EX equipped with APPI-source operating in positive ionmode. The HPLC consisted of Shimadzu LC10-ADvp LC pumps, SPD-M20A PDAdetector (operating at 254 nM) and SCL-10A system controller.Autosampler was Gilson Autosampler Gilson 215 Column Oven JonesChromatography 7990R ELSD Sedere Sedex 85 Column Waters Symmetry C-18Particle size 3.5 micrometer Dimension 30 * 4.6 mm ID Injection volume10 microL Column temperature 60° C. Flow 3.0 mL/min Mobile phases A0.05% TFA in water B 0.05% TFA in methanol Total run time 2.8 minGradient non-linear UV Detection Wavelength 254 nm ELSD DetectionTemperature: 50° C. Gas Pressure: 4.4 bar Time Gradient 0.01 min 17% Bin A 0.27 min 28% B in A 0.53 min 39% B in A 0.80 min 50% B in A 1.07min 59% Bin A 1.34 min 68% B in A 1.60 min 78% B in A 1.87 min 86% B inA 2.14 min 93% B in A 2.38 min 100% B 2.40 min 17% B in A 2.80 min 17% Bin A

Description of Chiral HPLC Methods

The enantiomeric purity was assayed on a Hewlett Packard 1100 seriessystem equipped with a diode array detector and using ChemStation for LCRev. A.08.03[847]. The HPLC method parameters are described in the tablebelow (Table 2). Compound (X) has a retention time around 13.6-13.7 minwhile its enantiomer,4-((1S,3R)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine,elutes at 8.5-8.6 min.

TABLE 2 Methods for Chiral HPLC Analysis 1-3 mg/mL in hexane/ SamplePreparation 2-propanol (80/20 v/v) Column: Chiralpak ADH 5 microm 250 ×4.6 mm Column Temperature (° C.): 30 Injection (microL): 5 Detection:240, 8 Wavelength, Bandwidth( nm): Total run-time 30 min Flow Rate (mL ·min⁻¹): 0.6 Mobile Phase hexane/2-propanol/diethylamine/ propionic acid90/10/0.2/2

Example 1 Preparation of4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine.butanedioicacid (Compound (I).butanedioic acid salt)

1-((1R,3S)-6-Chloro-3-phenyl-indan-1-yl)-3,3-dimethyl-piperazinehydrochloride (11.1 g) was dissolved in a mixture of toluene (74 mL) andwater (74 mL). Preparation of1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-dimethyl-piperazinehydrochloride is disclosed in the patent literature (Dahl, WøhlkNielsen, Suteu, Robin, Brøsen WO2006/086984 A1; Bang-Andersen, Bøgesø,Jensen, Svane, Dahl, Howells, Lyngsø, Mow WO2005/016901 A1; each hereinincorporated by reference in its entirety). 12.0 M of potassiumhydroxide in water (5.38 mL), tetra-N-butylammonium bromide (1.42 g),and d₃-iodomethane (Aldrich catalog #176036; 2.4 mL) were added and themixture was stirred at room temperature for 18 hours (Scheme 8). Themixture was filtered through a glass filter into a separatory funnel.The solid on the filter was washed with toluene (50 mL) into theseparatory funnel. The aqueous layer was extracted with toluene (100 mL)and the combined organic layers were washed with concentrated aqueousammonia (100 mL) and subsequently with water (100 mL) before it wasdried over sodium sulfate, filtered, and concentrated in vacuumaffording a slightly yellow oil. The oil was cooled to −78° C. undervacuum which solidified the oil. Upon warming to room temperature theoil became a semi-solid.

This material was dissolved in acetone (30 mL); in a separate flaskbutanedioic acid (3.46 g) was suspended in acetone (30 mL) and warmed toreflux (not all of the diacid went into solution). The acid suspensionwas added to the solution of the crude product and additional acetone(50 mL) was added to the butanedioic acid residue and then poured intosolution. The mixture was stirred overnight. Partial precipitation hadoccurred overnight, and the mixture was concentrated in vacuum. Theresidue was re-dissolved in acetone (70 mL) and warmed to reflux andallowed to cool to room temperature and stirred for 2 hours.

The mixture was filtered affording4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine.butanedioicacid (Compound (I).butanedioic acid salt; 7.61 g). LC-MS (method 131):RT(UV) 1.57 min; UV/ELS purity 100%/100%; mass observed 358.0.Incorporation of three deuterium atoms >99%. The proton-decoupled ¹³CNMR spectrum showed a heptet around 36.4 ppm corresponding to thedeuterated M2 metabolic site; this signal collapsed to a singlet in theproton- and deuterium-decoupled ¹³C NMR spectrum. All other signals weresinglets in both spectra. Optical purity >95% ee.

Example 2 Alternative method of preparation of4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine.butanedioicacid (Compound (I).butanedioic acid salt)

The free base of1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-dimethyl-piperazine wasprepared from the corresponding hydrochloride salt by partitioning 23.4g of the salt between a mixture of water (100 mL), concentrated aqueouspotassium hydroxide (40 mL), and toluene (250 mL). The organic layer waswashed with a mixture of water (50 mL) and concentrated aqueouspotassium hydroxide (10 mL). The combined aqueous layers were extractedwith toluene (75 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuum affording the free base of1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-dimethyl-piperazine (21.0g) as a colorless oil. This material was dissolved in a mixture oftoluene (150 mL) and water (150 mL), before 12.0 M aqueous potassiumhydroxide (11.3 mL), tetra-N-butylammonium bromide (2.98 g), andd₃-iodomethane (4.9 mL) were added and mixture was stirred at roomtemperature for 18 hours.

Work-up and purification was performed as described above and afforded4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine.butanedioicacid (Compound (I).butanedioic acid salt; 14.34 g; 48.9%).

Example 3 Preparation of4-((1R,3S)-6-chloro-3-phenyl-d₅-indan-1-yl)-1,2,2-trimethyl-piperazine(Compound (II)) and4-((1R,3S)-6-chloro-3-phenyl-d₅-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine(Compound (IV))

To a solution of compound A (57 g) in tetrahydrofuran (600 mL) was addedtriethylamine (30 mL) dropwise over 30 min. The reaction mixture waskept at room temperature for 3 hours. The precipitated solid wasfiltered and the filtrate was concentrated in vacuo. The residue wasreprecipitated from diethyl ether to afford compound B (31 g) as ayellow solid. To a solution of compound phenyl-d₅-boronic acid (25 g) in1,4-dioxane/water (900 mL/90 mL) was added [Rh(ndb)₂]BF₄ (1.3 g),racemic BINAP (2.1 g) and triethylamine (14 mL), then the reactionmixture was kept at room temperature for 2 hours under N₂. Then compoundindenone (19 g) was added, and the resulting mixture was heated to 100°C. for 3 hours. The precipitated solid was filtered off. The filtratewas concentrated in vacuo. The residue was purified by chromatography toafford indanone C (10 g).

13.4 kg 3-Bromo-6-chloro-indan-1-one (A; for references on thismaterial, see: Bøgesø EP 35363 A1 19810909 and Kehler, Juhl, Püschl, WO2008025361; each herein incorporated by reference in its entirety) wasdissolved in tetrahydrofuran (170.8 L), and the solution was cooled to0-5° C. (Scheme 9). Triethylamine (9.1 L) was added over 0.5 h. Themixture was stirred at 0-5° C. for 5 hours before an additional portionof triethylamine (2.48 L) was added over 0.5 hour, and stirring wascontinued for 2 hours. The mixture was filtered, and the filtrate wasconcentrated to 30 L before n-heptane (102 L) was added. The volume wasreduced to 60 L. More n-heptane (203 L) was added, and the mixture wasstirred for 1 hour. Silica gel (17.2 kg) was added. The mixture wasfiltered, and the residual solid was washed with n-heptane (100 L). Thecombined filtrates were concentrated to 30 L and stirred at 0-5° C. for1 hour. The mixture was centrifuged, and the residual solid was dried toafford 6-chloro-inden-1-one (compound B; 2.42 kg) sufficiently pure forthe next step.

2-Methyl-tetrahydrofuran (85 L) and N,N-dimethyl acetamide (12.4 L) wereadded to a reactor followed by potassium acetate (10.9 kg) andbis(pinacolato)diboron (14.8 kg). The resulting mixture was stirred for0.5 hour. Pd(dppf)Cl₂-DCM (0.91 kg) was added followed bybromobenzene-d₅ (9.0 kg) and 2-methyl-tetrahydrofuran (12.2 L). Themixture was heated to 80-85° C. for 3 hours, before the temperature wasreduced to ambient temperature. The crude mixture was filtered viakieselguhr and silica gel. The filter-cake was washed with2-methyl-tetrahydrofuran (31 L). The combined filtrates wereconcentrated to approximately 25 L while maintaining the temperaturebelow 35° C. n-Heptane (52 L) and 7% aqueous NaHCO₃ (31 L) were added,and the mixture was stirred for 0.5 hour. The organic layer was stirredwith 7% aqueous NaHCO₃ (31 L) for 0.5 hour. The combined aqueous layerswere extracted with n-heptane (22 L) over 0.5 hour. The combined organicextracts were washed with 25% aqueous NaCl (50 L) over 0.5 hour. Theorganic layer was concentrated while maintaining the temperature below35° C. to afford 4,4,5,5-tetramethyl-2-d₅-phenyl-[1,3,2]dioxaborolane(compound B′; 10.5 kg) sufficiently pure for the next step.

To a reactor was added sequentially 1,4-dioxane (85 L),6-chloro-inden-1-one (compound B; 9.09 kg prepared in a similar mannerto the one described above), 1,5-cyclooctadiene (0.2 L),bis(norbornadiene)rhodium(I) tetrafluoroborate (0.52 kg), triethylamine(5.5 L), 4,4,5,5-tetramethyl-2-d₅-phenyl-[1,3,2]dioxaborolane (compoundB′; 6.5 kg), and 1,4-dioxane (26 L). The mixture was heated to 48-53° C.and stirred at that temperature for 5 hours. The reaction was quenchedby the addition of 2M aqueous HCl (13 kg). Then n-heptane (110 L),methyl tert-butyl ether (32 L), and water (90 L) were added, and theresulting mixture was stirred for 0.3 hour. The organic layer was washedwith water (90 L) over 0.3 hour. The combined aqueous layers wereextracted with a mixture of methyl tert-butyl ether (30 L) and n-heptane(57 L) over 0.3 hour. The combined organic layers were filtered throughsilica gel (13 kg). The filter-cake was washed with a 2:1 mixture ofn-heptane and methyl tert-butyl ether (19.5 kg). The filtrate wasconcentrated to approximately 25 L. n-Heptane (45 L) was added, and thevolume was reduced to approximately 25 L. n-Heptane (45 L) was added,and the volume was reduced to approximately 35 L. The mixture wasstirred at 0-5° C. for 3 hours. The mixture was centrifuged, and theresidual solid was dried to afford racemic6-chloro-3-d₅-phenyl-indan-1-one (compound C; 8.4 kg) sufficiently purefor the next step.

Tetrahydrofuran (90 L) was added to a reactor followed by water (10 L)and 6-chloro-3-d₅-phenyl-indan-1-one (compound C; 7.73 kg) (Scheme 10).The mixture was cooled to −35-−30° C. Sodium borohydride (1.5 kg) wasadded portion-wise while maintaining the temperature at −35-−30° C. Theresulting mixture was stirred at −35-−30° C. for 5 hours before it wasallowed to warm to ambient temperature. Excess sodium borohydride wasquenched by the addition of 2M aqueous HCl (7.6 kg) while maintainingthe temperature below 45° C. Water (17 L) and methyl tert-butyl ether(67 L) were added and the mixture was stirred for 0.3 hour. The aq layerwas extracted with methyl tert-butyl ether (39 L) over 0.3 hour. Thecombined organic layers were washed with brine (36 kg) over 0.3 hour.The organic layer was filtered through silica gel (6.4 kg). Thefilter-cake was washed with methyl tert-butyl ether (20 L). The combinedfiltrates were concentrated to approximately 30 L while maintaining thetemperature below 45° C. n-Heptane (55 L) was added and the resultingmixture was concentrated to approximately 30 L while maintaining thetemperature below 45° C. The resulting mixture was stirred at 0-5° C.for 2 hours. The mixture was centrifuged, and the filter-cake was washedwith n-heptane (12 L) before it was centrifuged again. The residualsolid was dried to afford crude D. 4.87 kg of this material wasdissolved in methyl tert-butyl ether (20 L) and dried over Na₂SO₄ (2 kg)over 0.25 hour. The mixture was filtered, and the filter-cake was washedwith methyl tert-butyl ether (4.4 L). The combined filtrate wasconcentrated to approximately 20 L while maintaining the temperaturebelow 45° C. n-Heptane (32 L) was added and the mixture was toapproximately 25 L while maintaining the temperature below 45° C.n-Heptane (16 L) was added and the mixture was to approximately 20 Lwhile maintaining the temperature below 45° C. The solid was filteredoff and dried to afford racemic cis-6-chloro-3-d₅-phenyl-indan-1-ol(compound D; 4.99 kg) sufficiently pure for the next step.

To a solution of racemic cis-6-chloro-3-d₅-phenyl-indan-1-ol (compoundD; 50 g) in 2-isopropoxypropane (200 mL) was added vinyl butyrate (120mL) and Novozym-435 (15 g). The mixture was kept at ambient temperaturefor 2 days. The solid was filtered off. The filtrate was evaporated andpurified by chromatography on silica gel to afford(1S,3S)-6-chloro-3-d₅-phenyl-indan-1-ol (compound E; 13 g) sufficientlypure for the next step.

To a solution of (1S,3S)-6-chloro-3-d₅-phenyl-indan-1-ol (compound E; 7g) in THF (100 mL) was treated with SOCl₂ (6.6 g) at ambient temperatureovernight. The mixture was poured into ice-cold water, and extractedwith ethyl acetate. The organic layer was washed with brine. The organiclayer was dried over Na₂SO₄, filtered, and concentrated in vacuo toafford the intermediate chloride (7.5 g). 3.5 g of this material wasdissolved in 2-butanone (50 mL) and reacted with 2,2-dimethyl-piperazine(1.7 g) in the presence of K₂CO₃ (2.7 g) at reflux overnight. The solidwas filtered off. The filtrate was concentrated in vacuo and the residuewas purified by preparative HPLC on a Shimadzu FRC-10A instrument fittedwith a Synergi C18 column (250 mm*50 mm, 10 microm) using water andacetonitrile (containing 0.1% TFA, v/v) as the eluent to afford1-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-3,3-dimethyl-piperazine(compound F; 2.6 g) sufficiently pure for the next step.

To a solution of1-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-3,3-dimethyl-piperazine(compound F; 2.2 g) in HCHO/HCOOH (3 mL/3 mL) was refluxed overnight.The volatiles were removed in vacuo. The residue was partitioned betweenethyl acetate and 10% aq NaOH. The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford4-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine(Compound (II); 1.89 g). LC-MS (method WXV-AB05): RT(UV) 2.43 min;UV/ELS purity 95.1%/99.6%; mass observed 360.2. Incorporation of fivedeuterium atoms >95%. The proton-decoupled ¹³C NMR spectrum showed threetriplets around 126.1, 127.2, and 128.2 ppm corresponding to thedeuterated M3 metabolic sites; these signal collapsed to three singletsin the proton- and deuterium-decoupled ¹³C NMR spectrum. All othersignals were singlets in both spectra. Optical purity >95% ee.

To a solution of1-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-3,3-dimethyl-piperazine(compound F; 3.0 g) in DCDO/DCOOD (4 mL/4 mL) was refluxed overnight.The volatiles were removed in vacuo. The residue was partitioned betweenethyl acetate and 10% aq NaOH. The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford4-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-1-d₃-methyl-2,2-diimethyl-piperazine(Compound (IV); 2.14 g). LC-MS (method WXV-AB10): RT(UV) 2.06 min;UV/ELS purity 98%/100%; mass observed 363.3. Incorporation of eightdeuterium atoms >94%. The proton-decoupled ¹³C NMR spectrum showed aheptet around 36.4 ppm corresponding to the deuterated M2 metabolicsite; this signal collapsed to a singlet in the proton- anddeuterium-decoupled ¹³C NMR spectrum. The proton-decoupled ¹³C NMRspectrum further showed three triplets around 126.1, 127.2, and 128.2ppm corresponding to the deuterated M3 metabolic sites; these signalcollapsed to three singlets in the proton- and deuterium-decoupled ¹³CNMR spectrum. All other signals were singlets in both spectra. Opticalpurity >95% ee.

Example 4 Preparation of4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine-6,6-d₂(Compound (III)),4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine-6,6-d₂(Compound (V)),4-((1R,3S)-6-chloro-3-phenyl-d₅-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine-6,6-d₂(Compound (VI)), and4-((1R,3S)-6-chloro-3-phenyl-d₅-indan-1-yl)-1,2,2-trimethyl-piperazine-6,6-d₂(Compound (VII)

2-Amino-2-methyl-propionic acid (50.0 g) was suspended in a mixture ofmethanol and triethylamine (9:1, 1.2 L) (Scheme 11). 1M aqueous NaOH(450 mL) was added with stirring until all solid was dissolved.Di-tert-butyl dicarbonate (Boc₂O; 214.0 g) was added, and the mixturewas stirred at ambient temperature overnight. The organic volatiles wereremoved in vacuo. EtOAc (500 mL) was added. The organic layer was washedwith brine and dried over Na₂SO₄, filtered, then concentrated to afford2-tert-butoxycarbonylamino-2-methyl-propionic acid (compound K; 90 g) asa white solid which was used directly in next step directly.

A mixture of afford 2-tert-butoxycarbonylamino-2-methyl-propionic acid(compound K; 60.0 g) and 1-ethyl-3(3-dimethylaminopropyl) carbodiimidehydrochloride (EDC.HCl; 86.4 g) in dichloromethane (900 mL) was stirredat ambient temperature, then N,O-dimethyl hydroxylamine hydrochloride(35.3 g) and triethylamine (150 mL) were added. The resulting mixturewas stirred at ambient temperature for 3 days. Water was added and mostof volatiles were removed in vacuo. The residue was partitioned betweenDCM and aqueous NaHCO₃. The organic layer was washed with 3M aqueousHCl, subsequently with brine before it was dried over Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by silica gelchromatography to give[1-(methoxy-methyl-carbamoyl)-1-methyl-ethyl]-carbamic acid tert-butylester (compound L; 28.2 g) as a white solid sufficiently pure for thenext step.

Lithium aluminum hydride (7.8 g) was added to a stirred solution of[1-(methoxy-methyl-carbamoyl)-1-methyl-ethyl]-carbamic acid tert-butylester (compound L; 42.0 g) in dry diethyl ether (1.5 L) at −40° C. Thenstirred at that temperature for about 5 min. Excess LiAlH₄ was quenchedwith a solution of potassium hydrogen sulfate in water. The resultingmixture was partitioned between EtOAc and 3M aqueous HCl. The organiclayer was washed with sat. aqueous NaHCO₃, dried over Na₂SO₄, filtered,and concentrated in vacuo to afford (1,1-dimethyl-2-oxo-ethyl)-carbamicacid tert-butyl ester (compound M; 29 g) sufficiently pure for the nextstep.

Amino-acetic acid methyl ester hydrochloride (80.6 g) and Et₃N (160 mL)were dissolved in DCM (1000 mL) and stirred for 15 min to liberate theamine from the salt. Then a solution of1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (compound M;29.0 g) in DCM (600 mL) was added. The resulting mixture was stirred for0.5 hour at ambient temperature before NaBH(OAc)₃ (102 g) was added andthe mixture was stirred at ambient temperature overnight. Sat. aqueousNaHCO₃ was added. The aqueous layer was extracted with DCM. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by silica gel chromatography to afford(2-tert-butoxycarbonylamino-2-methyl-propylamino)-acetic acid methylester (compound N; 26.5 g) as white solid which was used directly in thenext step.

A mixture of (2-tert-butoxycarbonylamino-2-methyl-propylamino)-aceticacid methyl ester (compound N; 26.5 g) in DCM (800 mL) was stirred atambient temperature, TFA (180 mL) was added drop-wise. The mixture wasstirred at 30-40° C. for 5 h before it was concentrated in vacuo. Theresidue was partitioned between dissolved toluene and water. The organiclayer was dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidual solid was dissolved in a mixture of ethanol (400 mL) andmethanol (90 mL). K₂CO₃ (207 g) was added and the mixture was refluxedovernight. The mixture was cooled to room temperature. DCM (2500 mL) wasadded, and the mixture was stirred for 1 hour at ambient temperature.The solid was filtered off, and the filtrate was concentrated in vacuoto afford 6,6-dimethyl-piperazin-2-one (Compound I; 5.85 g) as a whitesolid sufficiently pure for the next step.

A solution of 6,6-dimethyl-piperazin-2-one (Compound I; 3.6 g) in THF(20 mL) was stirred at 0° C. Lithium aluminum deuteride (LiAlD₄; 3.6 g)was added then the mixture was refluxed overnight. The mixture wascooled to ambient temperature and Na₂SO₄ was added. The mixture wasstirred for 0.5 h before most of the volatiles were removed in vacuo.The residue was suspended in a saturated solution of HCl in EtOAc atambient temperature for 0.5 hour. The solid was filtered off and driedto afford to give 2,2-d₂-6,6-dimethyl-piperazine as thebis-hydrochloride salt (Compound J.2HCl; 5.3 g) sufficiently pure forthe next step.

To a solution of compound E′ (5 g) in THF (50 mL) was added SOCl₂ (4.7g), and the resulting mixture was stirred overnight at ambienttemperature (Scheme 12). The mixture was poured into ice-water andextracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄, filtered, and concentrated in vacuo to afford thecorresponding chloride (5.3 g) which was used directly in the next step.3.3 g of this material was dissolved in 2-butanone (50 mL) and reactedwith 2,2-d₂-6,6-dimethyl-piperazine (Compound J; 3 g) in the presence ofK₂CO₃ (8.28 g) at reflux overnight. The solid was filtered off. Thefiltrate was concentrated in vacuo. The residue was purified bypreparative HPLC on a Shimadzu FRC-10A instrument fitted with a SynergyC18 column (250 mm*50 mm, 10 microm) using water and acetonitrile(containing 0.1% TFA, v/v) as the eluents to afford1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine(Compound O; 1.7 g).

A solution of1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine(Compound O; 0.5 g) in HCHO/HCOOH (1 mL/1 mL) was refluxed overnight.The volatiles were removed in vacuo. The residue was partitioned betweenEtOAc and 10% aqueous NaOH. The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine-6,6-d₂(Compound (III); 0.33 g). LC-MS (method WXV-AB30): RT(UV) 1.42 min;UV/ELS purity 100%/100%; mass observed 357.2. Incorporation of twodeuterium atoms >97%. The proton-decoupled ¹³C NMR spectrum showed aquintet around 49.5 ppm corresponding to the deuterated M1 metabolicsite; this signal collapsed to a singlet in the proton- anddeuterium-decoupled ¹³C NMR spectrum. The proton-decoupled ¹³C NMRspectrum further showed three triplets around 126.1, 127.2, and 128.2ppm corresponding to the deuterated M3 metabolic sites; these signalcollapsed to three singlets in the proton- and deuterium-decoupled ¹³CNMR spectrum. All other signals were singlets in both spectra. Opticalpurity >95% ee.

A solution of1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine(Compound O; 0.7 g) in DCDO/DCOOD (1 mL/1 mL) was refluxed overnight.The volatiles were removed in vacuo. The residue was partitioned betweenEtOAc and 10% aqueous NaOH. The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine-6,6-d₂(Compound (V); 0.49 g). LC-MS (method WXVAB25): RT(UV) 2.13 min; UV/ELSpurity 100%/100%; mass observed 360.2. Incorporation of five deuteriumatoms >95%. The proton-decoupled ¹³C NMR spectrum showed a heptet around36.4 ppm corresponding to the deuterated M2 metabolic site; this signalcollapsed to a singlet in the proton- and deuterium-decoupled ¹³C NMRspectrum. The proton-decoupled ¹³C NMR spectrum further showed a quintetaround 49.5 ppm corresponding to the deuterated M1 metabolic site; thissignal collapsed to a singlet in the proton- and deuterium-decoupled ¹³CNMR spectrum. All other signals were singlets in both spectra. Opticalpurity >95% ee.

To a solution of (1S,3S)-6-chloro-3-d₅-phenyl-indan-1-ol (compound E; 7g) in THF (100 mL) was treated with SOCl₂ (6.6 g) at ambient temperatureovernight (Scheme 13). The mixture was poured into ice-cold water, andextracted with ethyl acetate. The organic layer was washed with brine.The organic layer was dried over Na₂SO₄, filtered, and concentrated invacuo to afford the intermediate chloride (7.5 g).

1.8 g of this material was dissolved in 2-butanone (30 mL) and reactedwith 2,2-d₂-6,6-dimethyl-piperazine (Compound J; 1.4 g) in the presenceof K₂CO₃ (5.5 g) at reflux overnight. The solid was filtered off. Thefiltrate was concentrated in vacuo. The residue was purified bypreparative HPLC on a Shimadzu FRC-10A instrument fitted with a SynergyC18 column (250 mm*50 mm, 10 microm) using water and acetonitrile(containing 0.1% TFA, v/v) as the eluents to afford1-((1R,3S)-6-Chloro-3-d₅-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine(Compound P; 1.7 g).

A solution of1-((1R,3S)-6-Chloro-3-d₅-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine(Compound P; 1 g) in DCDO/DCOOD (1.5 mL/1.5 mL) was refluxed overnight.The volatiles were removed in vacuo. The residue was partitioned betweenEtOAc and 10% aq NaOH. The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford4-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-1-d₃-methyl-2,2-dimethyl-piperazine-6,6-d₂(Compound (VI); 0.55 g). LC-MS (method WuXiAB25): RT(UV) 2.13 min;UV/ELS purity 98.2%/100%; mass observed 365.2. Incorporation of tendeuterium atoms >91%. The proton-decoupled ¹³C NMR spectrum showed aheptet around 36.4 ppm corresponding to the deuterated M2 metabolicsite; this signal collapsed to a singlet in the proton- anddeuterium-decoupled ¹³C NMR spectrum. The proton-decoupled ¹³C NMRspectrum further showed a quintet around 49.5 ppm corresponding to thedeuterated M1 metabolic site; this signal collapsed to a singlet in theproton- and deuterium-decoupled ¹³C NMR spectrum. The proton-decoupled¹³C NMR spectrum further showed three triplets around 126.1, 127.2, and128.2 ppm corresponding to the deuterated M3 metabolic sites; thesesignal collapsed to three singlets in the proton- anddeuterium-decoupled ¹³C NMR spectrum. All other signals were singlets inboth spectra. Optical purity >95% ee.

A solution of1-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine(Compound P; 0.7 g) in HCHO/HCOOH (1 mL/1 mL) was refluxed overnight.The volatiles were removed in vacuo. The residue was partitioned betweenEtOAc and 10% aqueous NaOH. The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford4-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-1-methyl-2,2-dimethyl-piperazine-6,6-d₂(Compound (VII); 0.47 g). LC-MS (method WXV-AB30): RT(UV) 1.33 min;UV/ELS purity 97.4%/100%; mass observed 362.3. Incorporation of sevendeuterium atoms >93%=. The proton-decoupled ¹³C NMR spectrum showed aquintet around 49.5 ppm corresponding to the deuterated M1 metabolicsite; this signal collapsed to a singlet in the proton- anddeuterium-decoupled ¹³C NMR spectrum. The proton-decoupled ¹³C NMRspectrum further showed three triplets around 126.1, 127.2, and 128.2ppm corresponding to the deuterated M3 metabolic sites; these signalcollapsed to three singlets in the proton- and deuterium-decoupled ¹³CNMR spectrum. All other signals were singlets in both spectra. Opticalpurity >95% ee.

Example 5 Description of NMR Determination of the Position(s) BearingDeuterium Rather than Hydrogen

NMR spectra were recorded on a Bruker 600-Avance-III spectrometerequipped with a 5 mm TCI cryoprobe operating at 150.91 MHz for ¹³C. Thesolvent CDCl₃ was used as internal reference for the proton-decoupledexperiments, while the proton- and inverse gated deuterium-decoupledspectra were recorded using gated lock. Difference(s) between the twospectra for the compounds of the invention determine(s) the position(s)of the deuterium atoms. When combining this information summarized inthe table below (Table 3) with the electrospray mass spectrometry datathat determined degree of deuteration, the structures of the compoundsof the invention can be assigned unambiguously.

TABLE 3 Carbon NMR data for compounds. M2 (methyl M1 (methylene M3(phenyl group @ ~126.1 ppm, group @ ~36.4 ppm) group @ ~49.5 ppm) ~127.2(2C), and ~128.2 (2C)) ¹³C NMR ¹³C NMR ¹³C NMR ¹³C NMR proton- and ¹³CNMR proton- and ¹³C NMR proton- and proton- deuterium- proton-deuterium- proton- deuterium- Cmpd. decoupled decoupled decoupleddecoupled decoupled decoupled (I) heptet singlet singlet singletsinglets singlets (II) singlet singlet singlet singlet 3 triplets 3singlets (III) singlet singlet quintet singlet 3 singlets 3 singlets(IV) heptet singlet singlet singlet 3 triplets 3 singlets (V) heptetsinglet quintet singlet 3 singlets 3 singlets (VI) heptet singletquintet singlet 3 triplets 3 singlets (VII) singlet singlet quintetsinglet 3 triplets 3 singlets Only NMR signals that ‘change’ as aconsequence of the presence of D rather than H in the compounds of theinvention are included in the table.

Relevant regions of the ¹³C proton-decoupled (lower spectrum) and ¹³Cproton- and deuterium-decoupled (upper spectrum) NMR spectra of Compound(II) and Compound (V) are shown in FIG. 3 as representative examples.Selected regions of the proton-decoupled and proton- anddeuterium-decoupled ¹³C NMR spectra of Compound (II) [FIG. 3A] andCompound (V) [FIG. 3B].

Example 6 Description of the Electrospray Mass Spectrometry to DetermineDegree of Deuteration

Instrumentation: Mass spectra of acidic, aqueous solutions of thecompounds were obtained on a Hewlett Packard quadrupole massspectrometer model 1100 LC-MSD. Liquid chromatography was performed onan Agilent 1100 HPLC-system coupled to the mass spectrometer.

Experimental: Solutions of the samples were made by dissolving approx. 2mg substance in 2 mL methanol+18 mL 10 mM ammonium formate pH 3.0.Subsequently the solutions were diluted 100-fold prior to analysis. Inorder to get a “clean” peak, the samples were chromatographed using aWaters X-bridge C18, 3.5 microm (150×2.1 mm) column, and 0.1%trifluoroacetic acid/acetonitrile 50/50 as mobile phase. This proceduregave one peak of the compound of interest eluting at ca. 3.6 min,containing both the deuterated compounds of the invention as well assmall quantities of deuterium-deficient species. The mass spectraobtained from these peaks were used to evaluate the speciation of thetarget molecules. The results were analyzed in percent of the totalamount of substance, adding up to 100%. The actual potency of thecompounds were not analyzed, merely the relative content of thedeuterium deficient species.

As a representative example, the mass spectrum of Compound (IV) is shownin FIG. 4. The isotopic pattern of the protonated Compound (V) [M+H]⁺with mass 363.1u (362.1u+1.0u) and the isotope ions 363.1u, 364.1u,365.1u and 366.1u was in the ratio 100:25.3:34.9:7.9; calculation forC₂₀H₂₂N₂ClD₈ gives the ratio 100:25.2:34.9:8.3. Furthermore, D₇-analogsand the D₃-analogs were observed at masses 362.1u and 358.1u,respectively. The signals at 364u, 365u and 366u are primarily due toprotonated molecules containing ¹³C and/or ³⁷Cl isotopes instead of ¹²Cand ³⁵Cl (due to the natural distribution). This data shows that theincorporation of eight deuterium atoms was greater than 94%.

Example 7 Experimental Binding Assays

Description of Human D₂ Binding Assay

The assay was performed as a SPA-based competition-binding in a 50 mMTris pH 7.4 assay buffer containing 120 mM NaCl, 5 mM KCl, 4 mM MgCl₂,1.5 mM CaCl₂, 1 mM EDTA.

1.5 nM ³H-raclopride (Perkin Elmer, NET 975) was mixed with testcompound before addition of 20 microg of a homogenised human D₂ receptormembrane-preparation and 0.25 mg SPA beads (WGA RPNQ 0001, Amersham) ina total volume of 90 microL. The assay plates were under agitationincubated for 60 minutes at room temperature and subsequently counted ina scintillation counter (TriLux, Wallac). The total binding, whichcomprised approximately 15% of added radioligand, was defined usingassay buffer, whereas the non-specific binding was defined in thepresence of 10 microM haloperidol. The non-specific binding constitutedapproximately 10% of the total binding.

Data points were expressed in percent of the specific binding of³H-Raclopride and the IC₅₀ values (concentration causing 50 percentinhibition of ³H-raclopride specific binding) were determined bynon-linear regression analysis using a sigmoidal variable slope curvefitting. The dissociation constant (K_(i)) was calculated from the ChengPrusoff equation (K_(i)=IC₅₀/(1+(L/K_(D))), where the concentration offree radioligand L is approximated to the concentration of added³H-raclopride in the assay. The K_(D) of ³H-raclopride was determined to1.5 nM from two independent saturation assays each performed withtriplicate determinations.

Description of Human D₁ Binding Assay

The assay was performed as a SPA-based competition-binding in a 50 mMTris pH 7.4 assay buffer containing 120 mM NaCl, 5 mM KCl, 4 mM MgCl₂,1.5 mM CaCl₂, 1 mM EDTA. Approximately 1 nM ³H—SCH23390 (Perkin Elmer,NET 930) was mixed with test compound before addition of 2.5 microg of ahomogenized human D₁ receptor membrane-preparation and 0.25 mg SPA beads(WGA RPNQ 0001, Amersham) in a total volume of 60 microL.

The assay plates were under agitation incubated for 60 minutes at roomtemperature before the plates were centrifuged and subsequently countedin a scintillation counter (TriLux, Wallac). The total binding, whichcomprised approximately 15% of added radioligand, was defined usingassay buffer whereas the non-specific binding was defined in thepresence of 10 microM haloperidol.

Data points were expressed in percent of the specific binding and theIC₅₀ values (concentration causing 50 percent inhibition of specificbinding) and were determined by non-linear regression analysis using asigmoidal variable slope curve fitting. The dissociation constant(K_(i)) was calculated from the Cheng Prusoff equation(K_(i)=IC₅₀/(1+(L/K_(D))), where the concentration of free radioligand Lis approximated to the concentration of added radio-ligand in the assay.

Description of Human 5-HT2_(A) Binding

The experiment was carried out at Cerep Contract Laboratories (Cat. ref.#471).

Compound (I) was also tested in an in vivo set up demonstrating centraleffects of the compound. By in vivo binding, the compound's in vivoaffinity for D₂ receptors was assessed and occupancy of 60% of thetarget was observed. Occupancy of D₂ receptors is closely linked toantipsychotic effects in animal models and in patients.

Description of In Vivo Binding to D₂ Receptors in Rat Brain

In vivo binding was carried out according to Andersen et al (Eur JPharmacol, (1987) 144:1-6; herein incorporated by reference in itsentirety) with a few modifications (Kapur S. et al, J Pharm Exp Ther,2003, 305, 625-631; herein incorporated by reference in its entirety).Briefly, 6 rats (male Wistar, 180-200 g) were treated with 20 mg/kg testcompound subcutaneous 30 minutes before receiving 9.4 micro Ci[³H]-raclopride intravenously via the tail vein.

15 minutes after the injection of the radio ligand the animals werekilled by cervical dislocation, the brain quickly removed and striatumand cerebellum dissected out and homogenized in 5 mL (cerebellum in 20mL) ice-cold buffer (50 mM K₃PO₄, pH 7.4). 1.0 mL of the homogenate wasfiltered through 0.1% PEI-soaked Whatman GF/C filters. This wascompleted within 60 seconds subsequent to the decapitation. Filters werewashed 2 times with 5 mL ice-cold buffer and counted in a scintillationcounter. A group of vehicle treated animals was used to determine[³H]-raclopride total binding in striatum and non-specific binding incerebellum. The homogenate was measured for protein content by the BCAprotein determination assay (Smith P. K. et al (1985) Anal. Biochem.,150: 6-85; herein incorporated by reference in its entirety).

Example 8 Investigation of the metabolism of4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine(Compound (X)) and4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine(Compound (I))

Cryopreserved dog (male Beagle dog) hepatocytes (1 million cells/mL insuspension, 50 microL/well) were pre-incubated for 15 minutes in a 96well plate at 37° C. water bath in DMEM high glucose buffered with 1MHEPES. The cell suspension was added with 50 microL test compounds(final concentration 0.1 or 1 microM of4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine(Compound (X)) or4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine(Compound (I)) and further incubated for 0, 15, 45, 75 and 120 minutes.The reaction was stopped by addition of 100 microL acetonitrile to thecell suspension, and the samples were then removed for LC-MS analysis ofthe desmethyl metabolite (Compound (XI)). Data were expressed as MS arearelative to an internal standard.

The results (FIG. 5 and FIG. 6) show that the amount of the desmethylmetabolite (Compound (XI)) produced in cryopreserved dog hepatocytes islower from the deuterated form (Compound (I)) than from the parentcompound (Compound (X)), both at a concentration of 0.1 micro M (FIG. 5)and at a concentration of 1 micro M (FIG. 6).

Example 9 Pharmacological Testing of Compounds

4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-d₃-methyl-2,2-dimethyl-piperazine(Compound (I)):

4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-d₃-methyl-2,2-dimethyl-piperazine(Compound (I)) was tested in three in vitro assays for dopamine D₁,dopamine D₂ and serotonin 5-HT_(2A) affinity.

The experiments were carried out as in the section Binding assays. Theexperimental results showed the following affinities for4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine:

D₁: Ki log mean=7.5 nM (pKi 0.88+/−0.15)

D₂: Ki log mean=34 nM (pKi 1.54+/−0.11)

5HT_(2A): IC50=1.14 nM

These binding affinities indicate that Compound (I) has biologicalactivity likely to exert antipsychotic effect.

Pharmacological Testing of Compound (II) and Compound (IV)

The experiments were carried out as described in the section “Bindingassays”. The experimental results for the two compounds are providedbelow.

Compounds (II) and Compound (IV) were tested in two in vitro assays fordopamine D₁ and dopamine D₂ affinity.

Compound (IV):

D₁: Ki log mean=26.1 nM (pKi 1.42+/−0.03)

D₂: Ki log mean=26.7 nM (pKi 1.43+/−0.04)

Compound (II):

D₁: Ki log mean=23.2 nM (pKi 1.37+/−0.03)

D₂: Ki log mean=26.5 nM (pKi 1.42+/−0.03)

These binding affinities indicate that Compound (II) and (IV) havebiological activity likely to exert antipsychotic effect.

Compound (II) and (IV) were also tested in an in vivo set updemonstrating central effects of the compound. By in vivo binding, thecompound's in vivo affinity for D₂ receptors was assessed and occupancyof 70% (Compound (IV)) and 75% (Compound (II)) of the target wasobserved. Occupancy of D₂ receptors is closely linked to antipsychoticeffects in animal models and in patients.

Compounds (I)-(VII) and (X) were assayed in a side-by-side analysis atCerep Contract Laboratories (Cat. Refs. #44, 46 and 471). Results ofreceptor binding is listed in Table 4.

TABLE 4 Binding of Compounds to D1, D2 and 5-HT2a. alternativealternative human human human D₁ receptor D₂ receptor 5-HT_(2A) Cmpd.binding (K_(i)) binding (K_(i)) (IC₅₀) (I) 0.10 nM 7.6 nM 0.37 nM; 1.14nM* (II) 0.20 nM 6.8 nM 1.1 nM (III) 0.36 nM 7.6 nM 1.1 nM (IV) 0.05 nM10 nM 0.25 nM (V) 0.10 nM 4.8 nM 0.61 nM (VI) 0.10 nM 3.7 nM 0.24 nM(VII) 0.14 nM 5.2 nM 0.33 nM (X) 0.22 nM 7 nM 0.79 nM *Compound (I) wastested twice in this assay.

Example 10 Metabolism Investigations in Pooled Human Liver Microsomes(HLM)

Pooled human liver microsomes (50 donors, from Xenotech) were incubatedwith 1 microM or 10 microM of compound at 37° C. The incubation mixturecontained 50 mM Tris-HCl, 154 mM KCl, 5 mM MgCl₂ and a NADPHregenerating system (1 mM NADP⁺, 5 mM isocitric acid, 1 unit/mLisocitric dehydrogenase, from Sigma-Aldrich). The protein concentrationwas 0.2 mg/mL and the final volume was 0.5 mL. Following a 10 minutepre-incubation, the reaction was initiated by adding Compound. After 0,15, 30, 60, 90, 120 and 180 minutes, the reactions were terminated bytransferring the subcellular fraction to 0.5 mL of stopping reagentcontaining internal standard. The incubations were carried out intriplicate. The samples were centrifuged at 4000 g (4° C., 15 min) andthe supernatants were analysed by HPLC-MS/MS. Data were expressed as MSarea relative to an internal standard.

The results are shown as the mean of triplicate determinations±SD. FIG.7 and FIG. 8 show that the amount of the desmethyl metabolite producedin human liver microsomes is lower from the deuterated form (Compound(II) and Compound (IV)) than from the non-deuterated compound (Compound(X)), both at a concentration of 1 microM (FIG. 7) and at aconcentration of 10 microM (FIG. 8). Results for Compound (III) areshown in FIG. 9. Results for Compounds (V)-(VII) are shown in FIGS.10-12, respectively. The desmethyl metabolites of compounds (II), (IV)and (X) are compounds (XX) and (XI), respectively (see FIG. 13).

Investigations Using Recombinant Human Liver CYP2C19 and CYP3A4

Recombinant human liver CYP2C19 or CYP3A4 isoenzymes (from BDbiosciences) were incubated with 1 microM or 10 microM Compound (X),Compound (II) or Compound (IV) at 37° C. The incubation mixturecontained 50 mM Tris-HCl, 154 mM KCl, 5 mM MgCl₂ and a NADPHregenerating system (1 mM NADP⁺, 5 mM isocitric acid, 1 unit/mLisocitric dehydrogenase, from Sigma-Aldrich). The protein concentrationwas 0.5 mg/mL and the final volume was 0.5 mL. Following a 10 minutespre-incubation, the reaction was initiated by adding Compound (X),Compound (II) and/or Compound (IV). After 0, 15, 30, 60, 90, 120 and 180minutes the reactions were terminated by transferring the subcellularfraction to 0.5 mL of stopping reagent containing internal standard. Theincubations were carried out in triplicate. The samples were centrifugedat 4000 g (4° C., 15 minutes) and the supernatants were analyzed byHPLC-MS/MS. Data were expressed as MS area relative to an internalstandard.

The results (FIG. 14 and FIG. 15) show that the amount of the desmethylmetabolite produced following incubation with recombinant human liverCYP2C19 enzymes is lower from the deuterated forms (Compound (II) andCompound (IV)) than from the non-deuterated compound (Compound (X)),both at a concentration of 10 micro M (FIG. 14, Compound (II)) and at aconcentration of 1 micro M (FIG. 15, Compound (IV)). Correspondingresults were obtained for Compound (II) at a concentration of 1 micro Mand for Compound (IV) at a concentration of 10 micro M.

Correspondingly, the amount of the desmethyl metabolite produced byincubation with recombinant human liver CYP3A4 enzymes is lower from thedeuterated forms (Compound (II) and (IV)) than from the non-deuteratedcompound (Compound (X)), both at a concentration of 1 micro M and 10micro M.

Example 11 Pharmacology of Compound (IV)

PCP-Induced Hyperactivity

Compound (IV) dose-dependently reverses PCP-induced hyperactivity inmice, indicative of antipsychotic efficacy (FIG. 16). Compound (IV)hydrogen tartrate was administered subcutaneous (s.c.) 30 minutes beforethe test. PCP hydrochloride (2.3 mg/kg) was administered s.c. justbefore the test. Locomotor activity was measured for 60 minutes asnumber of beam breaks (counts). Eight to 16 male mice were used in eachgroup. ## indicates P<0.01 versus Vehicle-PCP (One-way analysis ofvariance [ANOVA] followed by Bonferroni post-hoc test). PCP is blockingNMDA receptors and as such is used to model the hypo-glutamatergic staterelated to schizophrenia. PCP produces behavioural effects in animalsreminiscent of positive, negative, and cognitive symptoms ofschizophrenia patients (Jentsch, J. D. and Roth, R. H.Neuropsychopharmacology 1999; 20: 201-225; herein incorporated byreference in its entirety). PCP-induced hyperactivity is commonly usedas an assay for evaluation of antipsychotic compounds (Jackson, D. M. etal., Pharmacol Biochem Behav. 1994; 48: 465-471; herein incorporated byreference in its entirety).

Catalepsy

Catalepsy is thought to reflect drug-induced suppression of the abilityto initiate a behavioral response. The catalepsy test in rats is acommon and widely used preclinical screening test for the EPS liabilityof potentially antipsychotic drugs. Although catalepsy is usuallyassessed following acute drug administration, the test has proven to bea reliable predictor for the propensity of an antipsychotic drug toinduce EPS (that is, pseudo parkinsonism, dystonia) in humans (Elliott,P. J. et al, J. Neural. Transm. Park. Dis. Dement. Sect. 1990; 2: 79-89;herein incorporated by reference in its entirety).

Compound (IV) dose-dependently induced catalepsy in rats suggestive ofEPS liability. The minimal effective dose inducing catalepsy was 10mg/kg (FIG. 17). Compound (IV) tartrate was administered s.c. 30 minutesbefore the test. Eight male Sprague Dawley rats were used in each group.# indicates P<0.05, ## indicates P<0.01 versus vehicle (One-way ANOVAfollowed by Bonferroni post-hoc test). This dose is 100 times higherthan the dose indicating antipsychotic activity (FIG. 16).

Example 12 Human Pharmacokinetic Studies

The pharmacokinetics of Compound (IV) and Compound (X) were compared ina multiple oral dose study in healthy young men. The study participantsreceived daily doses of 3 mg Compound (IV) and 3 mg Compound (X) for 18days and blood samples were collected for 24 hours (one dosing interval)after the last dose to measure the exposure of both compounds and theirdemethylated metabolites, Compound (XX) and Compound (XI), respectively.

For all study participants, the area under the time-plasma concentrationcurve for the dosing interval (AUC 0-24) for Compound (IV) was higherthan that for Compound (X), mean 104 h*ng/mL vs 98 h*ng/mL. A consistentshift in the opposite direction was observed for the demethylatedmetabolites with mean AUC 0-24 of 117 h*ng/mL and 120 h*ng/ml forCompound (XX) and Compound (XI), respectively.

Example 13 Catalytic Enantioselective Synthesis of Ketone Intermediate

This example discloses the synthesis of(S)-6-chloro-3-phenyl(d₅)-indan-1-one, Compound (XV), and(S)-6-chloro-3-phenyl-indan-1-one, Compound (XVIII).

(S)-6-chloro-3-phenyl(d₅)-indan-1-one, Compound (XV), has proven to be avaluable building block in the synthesis of deuterated variants ofCompound (X) where the free phenyl group is deuterated.

General Experimental

Unless otherwise stated, all reactions were carried out under nitrogen.Reactions were monitored by thin-layer chromatography (TLC) analysis andLC-MS. All reagents were purchased and used without furtherpurification. Spots were visualized by exposure to ultraviolet (UV)light (254 nm), or by staining with a 5% solution of phosphomolybdenicacid (PMA) in ethanol or basic aqueous potassium permanganate (KMnO₄)and then heating. Column chromatography was carried out using Merck C60(40-63 μm, 230-240 mesh) silica gel. NMR spectra were recorded at 500 or600 MHz (¹H NMR), and calibrated to the residual solvent peak. Thefollowing abbreviations are used for NMR data: s, singlet; d, doublet;t, triplet; m, multiplet. Coupling constants are rounded to nearest 0.5Hz. Enantiomeric excess was determined by chiral HPLC.

LC-MS Method:

Acquity UPLC BEH C18 1.7 μm column; 2.1×50 mm operating at 60° C. withflow 1.2 mL/min of a binary gradient consisting of water+0.1% formicacid (A) and acetonitrile+5% water+0.1% formic acid (B).

Chiral HPLC Method:

Phenomenex Lux 5μ Cellulose-2 column; 250×4.6 mm operating at 30° C.with flow 0.6 mL/min of n-hexane:isopropanol:diethylamine, 90:10:0.1.

Synthesis of (S)-6-chloro-3-phenyl(d₅)-indan-1-one (Compound (XV))(Scheme 14)

1-phenyl(d₅)-vinyl trifluoromethanesulfonate (XII)

To a solution of acetophenone-d₅ (1.56 g, 12.5 mmol) in CH₂Cl₂ (25.0 mL)was added trifluoromethanesulfonic anhydride (2.52 mL, 15.0 mmol) atroom temperature. Then N,N-diisopropylethylamine (3.04 mL, 17.5 mmol)was added dropwise while the reaction mixture was cooled in an ice-waterbath. The reaction mixture was allowed to warm to room temperature, andit was stirred for 1.5 h. Trifluoromethanesulfonic anhydride (0.63 mL,3.74 mmol) was added followed by N,N-diisopropylethylamine (1.09 mL,6.24 mmol). The reaction mixture was stirred for 2 hours at roomtemperature. Toluene (25 mL) and silica gel (5 g) was added. The mixturewas concentrated in vacuo, and the resulting suspension was filteredthrough a pad of celite. The filter cake was washed with toluene (10mL), and the filtrate was evaporated to dryness in vacuo to yield crudeCompound (XII) (3.11 g, 82%, purity (NMR): approx. 85%) as a dark oil,that was used without further purification.

¹H NMR (600 MHz, CDCl₃) δ_(H) 5.38 (d, 1H, J=4.0 Hz), 5.62 (d, 1H, J=4.0Hz).

5-chloro-2-(1-phenyl(d₅)-vinyl)benzaldehyde (XIV) (Takagi, J.;Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Am. Chem. Soc. 2002, 124,8001-8006; Simeone, J. P.; Sowa, J. R. Jr. Tetrahedron 2007, 63,12646-12654; each herein incorporated by reference in its entirety).

To a solution of Compound (XII) (3.11 g, 10.3 mmol, purity (NMR):approx. 85%) in toluene was added triphenylphosphine (108 mg, 0.685mmol), bis(pinacolato)diboron (2.61 g, 10.3 mmol),bis(triphenylphosphine)palladium(II) chloride (240 mg, 0.342 mmol) andpotassium phenolate (1.92 g, 14.6 mmol). The reaction mixture wasstirred at 50° C. for 4 hours. This yielded Compound (XIII) in themixture, which was not isolated. The mixture was cooled to roomtemperature, and ethanol (10 mL) and water (5 mL) was added, followed bytetrakis(triphenylphosphine)palladium(0) (495 mg, 0.428 mmol), potassiumcarbonate (4.73 g, 34.2 mmol) and 2-bromo-5-chlorobenzaldehyde (1.88 g,8.56 mmol). The reaction mixture was stirred at 80° C. for 16 hours. Themixture was cooled to room temperature, and partitioned between water(50 mL) and toluene (50 mL).

The organic phase was separated and washed with water (50 mL) twice, andbrine. The organic phase was dried over MgSO₄, filtered and evaporatedto dryness in vacuo. The residue was subjected to purification by columnchromatography eluting with 80:1 n-heptane:EtOAc mixture to affordCompound (XIV) (1.66 g, 74%) as an orange oil.

¹H NMR (600 MHz, CDCl₃) δ_(H) 5.28 (d, 1H, J=0.5 Hz), 6.00 (d, 1H, J=0.5Hz), 7.30 (d, 1H, J=8.0 Hz), 7.56 (dd, 1H; J=2.5, 8.0 Hz), 7.96 (d, 1H,J=2.5 Hz); ¹³C NMR (150 MHz, CDCl₃) δ_(C) 118.7, 126.6 (t, J=24.0 Hz),127.5, 128.2 (t, J=24.0 Hz), 128.4 (t, J=24.0 Hz), 132.5, 133.7, 134.7,135.7, 140.3, 143.9, 144.8, 190.8; LC-MS (APPI): m/e calc. forC₁₅H₇D₅ClO [M+H]⁺ 248.1. found 248.1.

(S)-6-Chloro-3-phenyl(d₅)-indan-1-one (XV) (Kundu, K.; McCullagh, J. V.;Morehead, A. T. Jr. J. Am. Chem. Soc. 2005, 127, 16042-16043; hereinincorporated by reference in its entirety).

Hydrogen was bubbled through a N₂-flushed solution of((R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)(norbornadiene)rhodium(I)tetrafluoroborate (37 mg, 0.0404 mmol) in acetone (7.5 mL) for 10 min atroom temperature, during which the color of the solution changed fromorange to more brownish red. The flask containing the solution wassubsequently flushed briefly with N₂ gas. Then a solution of (XIV) (526mg, 2.02 mmol, purity (LC-MS): 95%) in acetone (7.5 mL) was added atroom temperature. The reaction mixture was stirred for 24 hours at roomtemperature. The reaction mixture was mixed with silica gel andevaporated to dryness in vacuo. The obtained material was loaded onto asilica gel column and the product was eluted with 10:1 n-heptane:EtOAcmixture to obtain Compound (XV) (495 mg, 96%, 96.0% ee) as a solid.

¹H NMR (500 MHz, CDCl₃) δ_(H) 2.72 (dd, 1H, J=4.0, 19.5 Hz), 3.27 (dd,1H, J=8.0, 19.5 Hz), 4.55 (dd, 1H, J=4.0, 8.0 Hz), 7.21 (d, 1H; J=8.0Hz), 7.52 (dd, 1H, J=2.0, 8.0 Hz), 7.77 (d, 1H, J=2.0 Hz); ¹³C NMR (125MHz, CDCl₃) δ_(C) 44.0, 47.2, 123.2, 126.8 (t, J=24.0 Hz), 127.3 (t,J=24.0 Hz), 128.7 (t, J=24.0 Hz), 134.4, 135.1, 138.2, 142.9, 156.0,206.4; LC-MS (APPI): m/e calc. for C₁₅H₇D₅ClO [M+H]⁺ 248.1. found 247.6.

Synthesis of (S)-6-chloro-3-phenyl-indan-1-one (XVIII) (Scheme 15)

(E)-1-(5-chloro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (XVI)

To an ice-cooled solution of sodium hydroxide (2.34 g, 58.6 mmol) inwater (17.0 mL) was added benzaldehyde (0.746 g, 7.03 mmol) and then asolution of 5-chloro-2-hydroxyacetophenone (1.00 g, 5.86 mmol) inmethanol (17.0 mL). The reaction mixture was allowed to warm to roomtemperature, and it was stirred for 24 hours. The bulk of the organicsolvent was removed by evaporation in vacuo. The aqueous residue wasextracted with EtOAc (3×30 mL). The combined extracts were washed withwater (50 mL) and brine (50 mL), dried over MgSO₄, filtered andevaporated to dryness in vacuo. The residue was dissolved in a minimumvolume of CH₂Cl₂, and n-pentane was added which resulted inprecipitation. The obtained suspension was filtered and the precipitatewas washed with little cold pentane, and dried in vacuo to affordCompound (XVI) (695 mg, 46%) as an orange solid.

¹H NMR (500 MHz, CDCl₃) δ_(H) 6.22 (d, 1H, J=9.0 Hz), 6.80 (dd, 1H,J=3.0, 9.0 Hz), 7.33 (t, 1H, J=7.5 Hz), 7.38-7.42 (m, 4H), 7.60 (d, 2H,J=7.5 Hz); 8.63 (d, 1H, J=16.0 Hz); ¹³C NMR (125 MHz, CDCl₃) δ_(C)110.6, 125.2, 127.8, 128.1, 128.8, 128.9, 129.4, 129.6, 1′33.0, 136.4,137.1, 174.5, 188.2.

Trifluoromethanesulfonic acid4-chloro-2-((E)-(3-phenyl-acryloyl))-phenyl ester (XVII)

To a solution of Compound (XVI) (517 mg, 2.00 mmol) in CH₂Cl₂ (10.0 mL)was added N,N-diisopropylethylamine (697 μL, 4.00 mmol).Trifluoromethanesulfonic anhydride (437 μL, 2.60 mmol) was addeddropwise at 0° C. The reaction mixture was stirred for 45 min at 0° C.Sat. aq. NH₄Cl (5 mL) and water (10 mL) was added, and the mixture wasstirred for 5 minutes. The organic phase was separated, and the aqueousphase was extracted with CH₂Cl₂ (10 mL). The combined extracts weredried over MgSO₄, filtered and evaporated to dryness in vacuo. Theresidue was purified by column chromatography eluting with 4:1n-heptane:EtOAc to yield (XVII) (757 mg, 97%) as an oil.

¹H NMR (500 MHz, CDCl₃) δ_(H) 7.16 (d, 1H, J=16.0 Hz), 7.34 (d, 1H,J=9.0 Hz), 7.40-7.47 (m, 3H), 7.57 (dd, 1H, J=2.5, 9.0 Hz), 7.60-7.62(m, 2H), 7.69 (d, 1H, 16.0 Hz), 7.72 (d, 1H, J=2.5 Hz); ¹³C NMR (125MHz, CDCl₃) δ_(C) 124.1, 124.2, 129.0, 129.2, 130.7, 131.5, 132.8,134.1, 134.6, 145.2, 147.8, 188.4.

(S)-6-Chloro-3-phenyl-indan-1-one (XVIII) (Minatti, A.; Zheng, X.;Buchwald, S. L. J. Org. Chem. 2007, 72, 9253-9258; herein incorporatedby reference in its entirety).

To a solution of Compound (XVII) (195 mg, 0.500 mmol) in DMF (2.0 mL)was added proton-sponge (214 mg, 1.00 mmol), palladium acetate (6 mg,0.025 mmol) and (R)-3,5-XylMeOBIPHEP (35 mg, 0.05 mmol) at rt. Thereaction mixture was stirred at 85° C. for 45 h. The mixture was cooledto rt, and diluted with TBME (15 mL). The mixture was washed three timeswith water (3×20 mL), and the organic phase was dried over MgSO₄,filtered and evaporated to dryness in vacuo. The residue was subjectedto column chromatography eluting with 10:1 n-heptane:EtOAc to yieldCompound (XVII) (94 mg, 77%, 64.0% ee).

¹H NMR (600 MHz, CDCl₃) δ_(H) 2.71 (dd, 1H, J=4.0, 19.5 Hz), 3.25 (dd,1H, J=8.0, 19.5 Hz), 4.54 (dd, 1H, J=4.0, 8.0 Hz), 7.10 (d, 2H, J=7.0Hz), 7.20 (d, 1H, J=8.0 Hz), 7.25 (t, 1H, J=7.5 Hz), 7.31 (t, 2H, J=7.5Hz), 7.50 (dd, 1H, J=2.0, 8.0 Hz), 7.75 (d, 2H, J=2.0 Hz); ¹³C NMR (150MHz, CDCl₃) δ_(C) 44.1, 47.2, 123.3, 127.3, 127.6, 128.3, 129.1, 134.4,135.2, 138.3, 143.1, 156.1, 204.5.

Enantioenrichment of Compound (XVIII) by Reprecipitation

Compound (XVII) (940 mg, 3.87 mmol, 96% ee) was dissolved in a minimumvolume of boiling ethanol (99% v/v). The resulting solution was allowedto cool slowly to rt by placing the glass flask containing the solutionin the air. A precipitate formed that was filtered from solution toyield Compound (XVIII) (700 mg, 99.9% ee, 74%). A second crop ofCompound (XVIII) could be obtained by cooling the filtrate in thefreezer (−8° C.) to yield Compound (XVIII) (80 mg, 98.6% ee, 9%).

Analytical data (NMR and LC-MS) for Compound (XVIII) were the same asthose reported above.

Example 14 Large Scale Production of Compound (IV)

The following process was developed for the large scale production ofthe hydrogen tartrate salt of Compound (IV).

Procedure:

-   -   1.) 2.01 kg (16.9 mol) thionylchloride and 7.2 kg        tetrahydrofuran are mixed and the reaction is cooled to 10-15°        C.    -   2.) a solution of 2.76 kg (11.1 mol) (XXII) in 7.2 kg THF is        slowly added and after completion 5.9 kg tetrahydrofuran is        added    -   3.) the reaction is stirred at 15° C. for approximately 90 hours    -   4.) 16.7 kg water is cooled to 11° C. and added slowly to the        reaction, afterwards 7.8 kg 27.7% aqueous sodium hydroxide is        added slowly, followed by 10 kg ethylacetate    -   5.) the mixture is stirred for 20-40 minutes    -   6.) the phases are separated and the organic phase is reduced to        a volume of approximately 6 L    -   7.) 16 kg methyl isobutylketone is added and the volume is        reduced to approximately 8 L    -   8.) 1.58 kg (11.4 mol) potassium carbonate, 1.69 kg (14.8 mol)        2,2-dimethylpiperazin and 13.6 kg methyl isobutyl ketone are        added    -   9.) the reaction is stirred 35 hours at 90-95° C.    -   10.) after cooling to room temperature 11 kg water is added and        the mixture is stirred for 30-60 minutes    -   11.) the phases are separated. 13.7 kg water is added to the        organic phase and the mixture is stirred slowly for 30-60        minutes    -   12.) the phases are separated and the organic phase is blank        filtered    -   13.) 5 kg methyl isobutyl ketone, 7.8 kg water and 5.9 kg 36%        aqueous hydrogen chloride are added and the mixture is stirred        at 50° C. for 30-60 minutes    -   14.) the phases are separated. 8 kg methyl isobutyl ketone is        added to the water phase and the mixture is cooled to 10-15° C.    -   15.) a mixture of 3.5 kg methyl isobutyl ketone and 7.8 kg 25%        aqueous ammonia are slowly added to the mixture and the reaction        is stirred at 20-25° C. for 60-90 minutes    -   16.) the phases are separated and the organic phase is washed        with 10.5 kg water    -   17.) the organic phase is reduced to 8 L    -   18.) 1.19 kg (10.25 mol) maleic acid and 9 kg methyl isobutyl        ketone are added and the reaction is afterwards warmed to 75-80°        C.    -   19.) after cooling to 10-15° C. the precipitate is filtered off        and washed with 10 kg methyl isobutyl ketone    -   20.) the solid is dried in a vacuum oven at 50° C. for        approximately 20 hours to give 3.47 kg (68% yield) of (XXV)        maleate.

NMR Data for (XXV) Maleate:

1H-NMR (dmso-d6, 600 MHz, ppm): 8.60 (bs, 2H, maleic acid), 7.39 (d, 1H,J=1.6 Hz), 7.29 (dd, 1H, J=8.0 Hz, J=1.8 Hz), 6.98 (d, 1H, J=8.2 Hz),6.04 (s, 2H, maleic acid), 4.56 (dd, 1H, J=8.1 Hz, J=4.9 Hz), 4.48 (dd,1H, J=8.6 Hz, J=6.2 Hz), 3.37 (bs, 1H), 3.16 (bs, 2H), 2.77 (bs, 1H),2.58-2.50 (m, 3H), 2.31 (d, 1H, J=12.0 Hz), 2.12 (ddd, 1H, J=13.8 Hz,J=8.0 Hz, J=6.0 Hz), 1.33 (s, 3H), 1.31 (s, 3H).

Procedure:

-   -   1.) 1.1 kg (2.38 mol) (XXV) maleate, 11 L methyl tertbutyl        ether, 1.8 L water and 1 L 25% aqueous ammonia are stirred for        1-2 hours    -   2.) the phases are separated and the organic phase is washed        with two times 2 L water    -   3.) a solution of 254 g (3.85 mol) 85% aqueous potassium        hydroxide and 1.5 L water is added to the organic phase,        followed by addition of 450 g (3.11 mol) methyl(d3)iodide (CD₃I)    -   4.) the reaction is stirred at 20-25° C. for 16-24 hours    -   5.) 2 L water are added and the precipitating by-product is        filtered off    -   6.) 0.8 L water and 0.2 L 25% aqueous ammonia are added to the        filtrate and the mixture is stirred for 20-40 minutes    -   7.) the phases are separated and the organic phase is washed        with 2 L water    -   8.) the phases are separated and 38 g (0.48 mol) acetylchloride        is added to the organic phase which is stirred for 20-40 minutes    -   9.) 0.8 L water and 0.2 L 25% aqueous ammonia are added and the        mixture is stirred for 20-40 minutes    -   10.) the phases are separated and the organic phase is washed        with 2 L water    -   11.) the organic phase is reduced to dryness and acetone is        added    -   12.) 225 g (1.91 mol) succinic acid and acetone are added so        that the reaction volume is approximately 6-6.5 L    -   13.) The reaction is warmed to reflux and afterwards cooled to        5-10° C.    -   14.) The precipitate is filtered off and washed with 1 L acetone    -   15.) the solid is dried in a vacuum oven at 50° C. for more than        16 hours to give 630 g (55% yield) of (XXVII) succinate

NMR Data for (XXVII) Succinate:

1H-NMR (dmso-d6, 600 MHz, ppm): 7.33 (d, 1H, J=1.9 Hz), 7.26 (dd, 1H,J=8.1 Hz, J=2.0 Hz), 6.95 (d, 1H, J=8.0 Hz), 4.46 (dd, 1H, J=8.0 Hz,J=5.1 Hz), 4.46 (dd, 1H, J=8.8 Hz, J=5.8 Hz), 2.65-2.56 (m, 4H),2.46-2.41 (m, 1H), 2.37 (s, 4H, succinic acid), 2.31 (bs, 1H), 2.13 (d,1H, J=10.9 Hz), 2.02 (ddd, 1H, J=13.7 Hz, J=7.8 Hz, J=6.0 Hz), 1.04 (s,3H), 1.02 (s, 3H).

Procedure:

-   -   1.) 1.0 kg (2.08 mol) (XXVII) succinate, 8 L ethyl acetate, 2 L        water and 1 L 25% aqueous ammonia are stirred for 0.5-1 hours    -   2.) the phases are separated and the organic phase is washed        with 2 L water    -   3.) the organic phase is reduced to approximately 1.5 L    -   4.) 10 L acetone and 312 g (2.08 mol) L(+)-tartaric acid are        added    -   5.) the reaction is warmed to reflux and afterwards cooled to        5-10° C.    -   6.) the precipitate is filtered off, washed with 1.2 L acetone    -   7.) the wet filtercake is recharged and 11 L absolute ethanol        are added    -   8.) the reaction is warmed to reflux and afterwards cooled to        5-10° C.    -   9.) the precipitate is filtered off and washed with 1.2 L        absolute ethanol    -   10.) the solid is dried in a vacuum oven at 50° C. for more than        16 hours to give 395 g (37% yield) of (IV) L(+)-hydrogen        tartrate.

NMR Data for (IV) L(+)-Hydrogen Tartrate:

1H-NMR (dmso-d6, 600 MHz, ppm): 7.36 (s, 1H), 7.27 (d, 1H, J=8.2 Hz),6.96 (d, 1H, J=8.2 Hz), 4.50 (dd, 1H, J=8.0 Hz, J=5.1 Hz), 4.45 (dd, 1H,J=8.5 Hz, J=5.8 Hz), 4.07 (s, 2H, tartrate), 2.95 (bs, 1H), 2.77 (bs,1H), 2.61-2.50 (m, 3H), 2.31 (d, 1H, J=11.7 Hz), 2.04 (ddd, 1H, J=13.7Hz, J=7.8 Hz, J=6.0 Hz) 1.21 (s, 3H), 1.18 (s, 3H).

Example 15 Physico-Chemical Characterization of Salts of Compound (IV)

pK_(a) and Log P/D of Compound (IV)

pK_(a) was determined by potentiometric titration of the base at ionstrength 0.16 using MeOH as co-solvent. Three series of three repeatedtitrations on the same solution of the sample was performed in aconventional way from low to high pH and a difference curve was createdfrom each of these titrations by blank subtraction. The apparentpK_(a)-value at each MeOH:water ratio is calculated from the differencecurves, and the pK_(a) value is determined by extrapolation to zero MeOHcontent.

The lower pK_(a) value is too low to be determined by potentiometrictitration as data only were found reliable down to ˜3. The high pK_(a)was determined to be 8.9±0.1.

The lower pK_(a) was determined by Dip Probe Absorption Spectroscopydetection during titration of the base at ion strength 0.16 using MeOHas co-solvent. The change in absorption spectra as a function ofionisation is used to calculate the pK_(a)-value. Two series of threerepeated titrations on the same solution of the sample was performedfrom low to high pH, with a photo diode array as additional detection.The apparent pK_(a)-value at each MeOH:water ratio is calculated byTarget factor analysis on the change in absorption spectra, and thepK_(a) value is determined by extrapolation to zero MeOH content.

Result: The lower pK_(a) was determined to be 2.5±0.1.

The log D profile was determined by titration at 27° C. and ion strengthof approx. 0.16. A series of three repeated titrations on the samesample in solution was performed, from low to high pH. The firsttitration was performed with a small amount of n-octanol present in thesolution, the second and third with increasing amounts.

A difference curve was created from each of these titrations by blanksubtraction, and from these difference curves, the apparent pK_(a)values (p_(o)K_(a)) were calculated. From the change in the apparentpK_(a) values (ΔpK_(a)) with the n-octanol:water ratio combined with thereal pK_(a) value, the Log P value was calculated and the Log D profilewas derived. The following values were determined: Log P=5.4±0.4 and LogD_(7.4)=3.9±0.4.

Melting Point Determined by DSC

The melting point of the (R,R)-hydrogen tartrate salt of Compound (IV)was determined using differential scanning calorimetry (DSC), using a TAinstruments DSC Q1000 heating the sample 5°/minute. The sample wasplaced in a covered pan with a punched pinhole.

The melting is characterized by onset and peak temperature of themelting endotherm, and the enthalpy of fusion is calculated from thearea of the peak. Based on the DSC thermogram an onset temperature of187.4° C. and a peak maximum at 189.4° C. was found. The enthalpy offusion was 96 J/g corresponding to 49 kJ/mol, however the thermogram isindicative that the melting happens under decomposition meaning that theenthalpy probably contain energy other than melting.

Solubility

Solubility of the (R,R)-hydrogen tartrate salt of Compound (IV) wasmeasured in aqueous solutions and in cyclodextrins with the followingresults (Table 5):

TABLE 5 Solubility of (R,R)-hydrogen tartrate salt of Compound (IV).Meas. conc. Solvent (mg base/ml) pH Hydrogen tartrate in water, 5° C.3.1 3.25 Hydrogen tartrate in water, RT 4.0 3.15 Hydrogen tartrate inwater, 37° C. 6.6 3.08 10% HPβCD 25.2 3.59 5% HPβCD, at RT 15.5 3.61 5%HPβCD, at 5° C. 12

Polymorphism

One solvent free crystal form of the hydrogen tartrate has beenisolated. The XRPD of this form is shown in FIG. 18, and designatedherein as “polymorph A”.

Salts of Compound (IV)

Four salts were prepared by precipitation of Compound (IV) from 99%EtOH.

Analytical data are given in the table below (Table 6).

TABLE 6 Data for salts of Compound (IV) Solubility Salt DSC (T_(onset) °C.) (mg/ml) pH Dihydrogen Degradation at 1.4 4.67 phosphate 250° C.Hydrogen fumarate 202.7° C. 1.2 4.10 Hydrogen maleate 150.4° C. 1.2 4.94Hydrogen malonate 145.0° C. followed 9.5 4.08 by degradation Hydrogentartrate 187° C. 4.0 3.15 Base 59.9 0.1 7.6 

Although the invention has been described and illustrated in theforegoing illustrative embodiments, it is understood that the presentdisclosure has been made only by way of example, and that numerouschanges in the details of implementation of the invention can be madewithout departing from the spirit and scope of the invention, which islimited only by the claims that follow. Features of the disclosedembodiments can be combined and/or rearranged in various ways within thescope and spirit of the invention to produce further embodiments thatare also within the scope of the invention. Those skilled in the artwill recognize, or be able to ascertain, using no more than routineexperimentation, numerous equivalents to the specific embodimentsdescribed specifically in this disclosure. Such equivalents are intendedto be encompassed in the scope of the following claims.

What is claimed:
 1. A process for the preparation of a compound offormula (S)-(XV):

comprising treatment of a compound of formula (XIV)

with((R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)(norbornadiene)rhodium(I)tetrafluoroborate.
 2. The process of claim 1, wherein the compound offormula (XIV) is obtained by a process comprising treating a compound offormula (XII)

with bis(pinacolato)diboron followed by 2-bromo-5-chlorobenzaldehyde. 3.The process of claim 1, wherein the compound of formula (XV) is obtainedin 96% enantomeric excess.
 4. A process for the preparation of acompound of formula (1R,3S)-(IV)-tartrate,

(1R,3S)-(IV)-tartrate comprising treatment of racemictrans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-1(d₃), 2,2-trimethylpiperazine with L-(+)-tartaric acid.
 5. The process of claim 4, wherein(1R,3S)-(IV)-tartrate is crystallized from ethanol.
 6. The process ofclaim 5, wherein racemictrans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-1(d₃), 2,2-trimethylpiperazine is generated from the corresponding succinate salt thereof.7. The process of claim 6, wherein racemictrans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-1(d₃), 2,2-trimethylpiperazine succinate is generated from the maleate salt oftrans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-3,3-dimethyl piperazine.
 8. Aproduct prepared by the process of claim
 1. 9. A product prepared by theprocess of claim
 4. 10. A polymorph of the hydrogen tartrate salt ofcompound (IV) having the XRPD pattern as shown in FIG.
 18. 11. Thepolymorph of claim 10, wherein the polymorph is a solvent free crystalform.